Aetiology of Significant Liver Test Abnormalities in a Single-Centre Cohort of People with Cystic Fibrosis Exposed to Elexacaftor/Tezacaftor/Ivacaftor, Utilizing the Updated RUCAM.

BACKGROUND: The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator elexacaftor/tezacaftor/ivacaftor (E/T/I) has been associated with substantial multisystem benefits for people with CF eligible for therapy. In a minority, tolerance has been limited by hepatic toxicity. It is unknown whether there may be particular risk factors for significant drug-induced elevation in transaminases. OBJECTIVE: We aimed to determine the cause of raised transaminases following the introduction of E/T/I, and whether E/T/I can safely be continued in some individuals with elevated transaminases. METHODS: At a large, single, adult CF centre, individuals with transaminases >3 × the upper limit of normal (ULN) since commencing E/T/I underwent clinical assessment to exclude known causes of raised transaminases. Where an alternative cause could not be identified, individuals were discussed with hepatology to advise on further investigations to establish aetiology in addition to calculation of the updated Roussel Uclaf Causality Assessment Method (RUCAM) score to assess causality grading of drug-induced liver injury (DILI) due to E/T/I, and to guide management of ongoing CFTR modulator therapy. RESULTS: Of 337 adults taking E/T/I for a median of 27 months, 19 (5.6%) had transaminases >3 × ULN. In 12 individuals, there was clear evidence of an aetiology unrelated to E/T/I (RUCAM scores -2 to 1 [excluded-unlikely]). Of the remaining cases, two had RUCAM scores in the 'possible' range and one had a RUCAM score in the 'probable' range. Liver biopsy was performed in four individuals, showing hepatic steatosis in one individual, normal histology in one individual, and hepatocyte necrosis suggestive of DILI in two individuals. E/T/I was suspended in those with hepatocyte necrosis, with one permanent discontinuation due to synthetic dysfunction. One individual with hepatocyte necrosis on histology was successfully re-established on E/T/I therapy. CONCLUSIONS: Alternative causes were identified in the majority of patients with clinically significant increases in transaminases following E/T/I, highlighting the importance of thorough investigation. Multidisciplinary assessment involving an experienced hepatologist is crucial in cases of diagnostic uncertainty or suggestion of significant DILI, as discontinuation of therapy can have significant consequences for individuals.

Effects of elexacaftor/tezacaftor/ivacaftor on liver fibrosis markers in adults with cystic fibrosis.

BACKGROUND: There are limited studies to date on the effects of elexacaftor/tezacaftor/ivacaftor (E/T/I) on markers of liver fibrosis in adults with cystic fibrosis (CF). This study aims to analyse changes in makers of liver fibrosis before and after initiation of E/T/I in CF adults. METHODS: Outcome measures of liver fibrosis, including liver stiffness measurement (LSM) using FibroScan, AST-to-platelet-ratio index (APRI) and gamma-GT-to-platelet-ratio (GPR) were available in 74 CF adults following initiation of E/T/I. This was compared to historical data collected in 2018 prior to UK availability of E/T/I. RESULTS: The median duration of E/T/I therapy at the time liver fibrosis markers were repeated was 21 (IQR: 17-25) months. There was an increase in APRI from historical measurement to follow-up but no change in LSM or GPR. There were no differences in change in fibrosis markers according to CF liver disease (CFLD) status, although those with a raised LSM at baseline (>6.8 kPa) (n = 14) had a significant reduction in LSM from historical measurement to follow-up versus those with a normal historical value (-3.3 kPa vs 0.25 kPa, p < 0.01). CONCLUSIONS: Apart from APRI, we found no changes in liver fibrosis outcomes after initiation of E/T/I in adults with CF. Those with a historical diagnosis of CFLD had no significant worsening or improvement of liver fibrosis markers. We did observe a reduction in LSM in those with liver nodularity, with an initial highest result suggesting a potential positive treatment effect of E/T/I in this category of those with severe CFLD.

Longitudinal effects of elexacaftor/tezacaftor/ivacaftor on liver tests at a large single adult cystic fibrosis centre.

BACKGROUND: Elexacaftor/tezacaftor/ivacaftor (E/T/I) therapy has resulted in substantial improvements in health status for many with cystic fibrosis. Monitoring of liver tests is recommended due to observed rises in transaminases in trials and cases of hepatotoxicity. Comprehensive data in large populations of unselected individuals and those with established CF related liver disease (CFLD) is lacking. METHODS: Patients prescribed E/T/I at a large, adult centre had liver tests monitored at least 3 monthly for 12 months. Changes in individual liver tests were analysed and abnormalities were compared in those with and without CFLD. RESULTS: 255 of 267 eligible patients were included. Mild rises in median ALT, AST and bilirubin from baseline to 3 months (all p < 0.001) within normal limits were noted which were sustained. There were no differences in changes in liver tests between those with or without CFLD. There was a significant difference in alkaline phosphatase for those with raised levels at baseline versus those with normal baseline level (-18.5 vs +2.0 IU/L, p = 0.002). Clinically significant rises in ALT and AST occurred in 8 (3.1%) and 6 (2.4%) cases respectively, with derangements in 2 individuals attributed to therapy. CONCLUSIONS: E/T/I leads to a mild, likely clinically insignificant increase in ALT, AST and bilirubin after 3 months which is sustained but does not appear to increase further in the vast majority. Underlying CFLD should not be a barrier to treatment. Although there was a reduction in ALP when elevated at baseline, this was not unique to those with pre-existing CFLD.

Cardiac involvement in cystic fibrosis evaluated using cardiopulmonary magnetic resonance.

Cystic fibrosis (CF) transmembrane conductance regulator is expressed in myocardium, but cardiac involvement in CF remains poorly understood. The recent development of a combined cardiopulmonary magnetic resonance imaging technology allows for a simultaneous interrogation of cardiac and pulmonary structure and function. The aim of this study was to investigate myocardial manifestations in adults with CF, both in a stable state and during an acute respiratory exacerbation, and to investigate the relationship between cardiac and pulmonary disease. Healthy adult volunteers (n = 12) and adults with CF (n = 10) were studied using a multiparametric cardiopulmonary magnetic resonance protocol. CF patients were scanned during an acute respiratory exacerbation and re-scanned when stable. Stable CF was associated with left ventricular dilatation and hypertrophy (LVH; left ventricular mass: CF 59 ± 9 g/m2 vs. control 50 ± 8 g/m2; p = 0.028). LVH was predominantly driven by extracellular myocardial matrix expansion (extracellular matrix mass: CF 27.5 ± 3.4 g vs. control 23.6 ± 5.2 g; p = 0.006; extracellular volume [ECV]: CF 27.6 [24.7-29.8]% vs. control 24.8 [22.9-26.0]%; p = 0.030). Acute CF was associated with an acute reduction in left ventricular function (ejection fraction: acute 57 ± 3% vs. stable 61 ± 5%; p = 0.025) and there was a suggestion of myocardial oedema. Myocardial oedema severity was strongly associated with the severity of airflow limitation (r = - 0.726, p = 0.017). Multiparametric cardiopulmonary magnetic resonance technology allows for a simultaneous interrogation of cardiac and pulmonary structure and function. Stable CF is associated with adverse myocardial remodelling, including left ventricular systolic dilatation and hypertrophy, driven by myocardial fibrosis. CF exacerbation is associated with acute myocardial contractile dysfunction. There is also a suggestion of myocardial oedema in the acute period which is related to pulmonary disease severity.

Thoracic movement screening in adults with cystic fibrosis: reliability of the Manchester musculoskeletal screening tool.

OBJECTIVES: The Manchester Musculoskeletal Screening Tool (MMST) is used internationally to screen for pain, postural changes, and urinary incontinence in adults with cystic fibrosis (CF). The tool has been validated for the outcome measures of pain and incontinence but not for the thoracic movement section. The aim of this study was to assess intra (single rater) and inter-rater (between rater) reliability of the thoracic movement screen section of the MMST. METHODS: This is a prospective reliability study. Digital videos of thoracic movement were taken of adults with CF during their annual musculoskeletal screening at a large UK Adult CF Center. Twelve physiotherapists independently watched the videos and scored the movements on two occasions, 2 weeks apart, using MMST. Cohen's kappa and Krippendorff alpha were used to establish intra- and inter-rater reliability. RESULTS: Intra-rater reliability using Cohen's kappa calculation ranged between 0.35 and 0.93. Eleven out of 12 physiotherapists had a moderate-substantial reliability score as assessed by the Landis Koch criteria. Percentage agreement for each physiotherapist ranged from 67%-97%. The inter-rater reliability was poor (Krippendorff alpha score = 0.422 (CI: 0.24-0.60)). CONCLUSION: The thoracic section of the MMST is reliable in adults with CF to highlight changes in posture and thoracic mobility that may go undetected or under-reported by the patient when repeated by the same clinician. However, the inter-rater variability is high, and it should not be considered reliable when carried out by different clinicians over time.

Kidney and combined kidney and pancreas transplantation may be under-utilized in cystic fibrosis.

Cystic fibrosis (CF) is a multisystem disorder and represents the most common inherited condition leading to death in Western countries. Previous reports of chronic kidney disease (CKD) in CF focus on cases post lung, or other solid organ, transplantation but CKD in CF patients pre transplantation is increasingly recognized as a challenging complication of CF. CKD can evolve as a sequel to acute kidney injury for example after prolonged treatment with aminoglycoside antibiotics during episodes of infection. Nephrolithiasis, diabetic nephropathy and a variety of glomerular lesions, such as amyloidosis and Immunoglobulin A nephropathy are also seen. Muscle depletion is common in CF, hence creatinine-based estimates of kidney function may underestimate the degree of renal impairment and lead to delayed diagnosis and management. Improved treatment options for CF patients have resulted in a sustained increase in life expectancy with increasing numbers of CF patients with CKD approaching end-stage renal failure prior to consideration of lung transplantation. We believe that kidney or combined kidney-pancreas transplantation are under-utilized in this population. We provide a brief primer on the landscape of CF and CKD and discuss transplant options. Suitable patients with CF and advanced CKD should be formally assessed for kidney or kidney-pancreas transplantation.

Meteorological Factors Influence the Presence of Fungi in the Air; A 14-Month Surveillance Study at an Adult Cystic Fibrosis Center.

Background: Cystic fibrosis is an inherited disease that predisposes to progressive lung damage. Cystic fibrosis patients are particularly prone to developing pulmonary infections. Fungal species are commonly isolated in lower airway samples from patients with cystic fibrosis. Fungal spores are prevalent in the air. Methods: We performed environmental air sampling surveillance at the Manchester Adult Cystic Fibrosis Centre, UK (MACFC) over a 14-month period to assess fungal growth inside and outside the CF center. Results: Airborne counts of fungal spores peaked from May to October, both in outdoor and indoor samples. Collection of meteorological data allowed us to correlate fungal presence in the air with elevated temperatures and low wind speeds. Additionally, we demonstrated patient rooms containing windows had elevated fungal counts compared to rooms not directly connected to the outdoors. Conclusions: This study suggests that airborne Aspergillus fumigatus spores were more abundant during the summer months of the survey period, which appeared to be driven by increased temperatures and lower wind speeds. Indoor counts directly correlated to outdoor A. fumigatus levels and were elevated in patient rooms that were directly connected to the outdoor environment via an openable window designed for ventilation purposes. Further studies are required to determine the clinical implications of these findings for cystic fibrosis patients who are predisposed to Aspergillus related diseases, and in particular whether there is seasonal influence on incidence of Aspergillus related conditions and if screening for such complications such be increased during summer months and precautions intensified for those with a known history of Aspergillus related disease.

Influenza B outbreak at an adult cystic fibrosis centre - Clinical impact and factors influencing spread.

INTRODUCTION: An outbreak of Influenza B occurred at a large United Kingdom (UK) regional adult cystic fibrosis (CF) centre in May 2016. This was late in the UK 2015-2016 influenza season and occurred on a specialist ward with strict infection control procedures. This study investigates the spread of influenza, clinical consequences and potential contributing factors. METHODS: Patient records, clinical status and pulmonary function data were reviewed for all inpatients during this period. Respiratory viral PCR results, influenza vaccination status of patients and staff, and environmental factors were also recorded. Affected patients were prospectively monitored for the following three months. RESULTS: 10 of 21 inpatients developed influenza B between 5th and 12th May 2016, an attack rate of 48%. All those characterised were confirmed as the same strain of influenza B/Victoria-lineage. Influenza infection resulted in a mean FEV1 reduction of 10.5% (SD 11.3, p = 0.012), which persisted at 3 months post infection (p = 0.003). Nine of the affected cases rooms were in close proximity on the ward while patients in the two isolation rooms with enhanced ventilation did not become infected. Ventilation measurements in affected rooms ranged from 1.75 to 2.10 air changes/hour, below national recommendations. Seventy percent of affected inpatients had received the 2015/16 trivalent seasonal influenza vaccine, which did not contain a B/Victoria-lineage influenza B virus. CONCLUSION: This influenza B outbreak in CF adults had a high attack rate and a significant clinical impact. Room ventilation and a limited protection from the seasonal influenza vaccine were possible contributory factors.

Lessons of the month 1: Salbutamol induced lactic acidosis: clinically recognised but often forgotten.

We present the case of an 83-year-old woman, with known asthma, admitted with increasing dyspnoea, wheeze and a productive cough. In addition to maintenance inhaled therapy, the patient was also on long-term mirtazapine and furosemide. Following acute treatment with nebulised salbutamol she became increasingly dyspnoeic and developed a metabolic acidosis with a significantly raised blood lactate level. After cessation of ß2-adrenergic medication, the patient's clinical condition improved with resolution of her lactic acidosis; salbutamol induced lactic acidosis was diagnosed. This clinical scenario is common but not well described. Here we discuss the mechanisms, investigation and management of raised serum lactate and lactic acidosis in the context of acute asthma and the possible interactions of polypharmacy and comorbidities in the acute medical setting.

Investigation of a Pandoraea apista cluster common to adult and paediatric cystic fibrosis patients attending two hospitals in the same city.

PURPOSE: We examined evidence for transmission of Pandorea apista among cystic fibrosis (CF) patients attending paediatric and adult services in one city who had previously been found to harbour related isolates by pulsed-field gel electrophoresis (PFGE). METHODOLOGY: The whole-genome sequences of 18 isolates from this cluster from 15 CF patients were examined, along with 2 cluster isolates from 2 other centres. The annotated sequence of one of these, Pa14367, was examined for virulence factors and antibiotic resistance-associated genes in comparison with data from a 'non-cluster' isolate, Pa16226. RESULTS: Single-nucleotide polymorphism (SNP) analysis suggested that cluster isolates from the same city differed from one another by a minimum of 1 and a maximum of 383 SNPs (an average of 213 SNPs; standard deviation: 18.5), while isolates from the 2 other hospitals differed from these by a minimum of 34 and 61 SNPs, respectively. Pa16226 differed from all cluster isolates by a minimum of 22 706 SNPs. Evidence for patient-to-patient transmission among isolates from the same city was relatively limited, although transmission from a common source could not be excluded. The annotated genomes of Pa14367 and Pa16226 carried putative integrative and conjugative elements (ICEs), coding for type IV secretion systems, and genes associated with heavy metal degradation and carbon dioxide fixation, and a wide selection of genes coding for efflux pumps, beta-lactamases and penicillin-binding proteins. CONCLUSION: Epidemiological analysis suggested that this cluster could not always be attributed to patient-to-patient transmission. The acquisition of ICE-related virulence factors may have had an impact on its prevalence.

Increased prevalence of Pneumocystis jirovecii colonisation in acute pulmonary exacerbations of cystic fibrosis.

OBJECTIVES: This study examined the prevalence of Pneumocystis jirovecii in the sputum of adults with cystic fibrosis during clinical stability and acute pulmonary exacerbation. METHODS: This was a prospective, longitudinal observational study of patients attending the Manchester Adult Cystic Fibrosis Centre. Sputum samples were analysed for P. jirovecii DNA using PCR at enrolment and up to 5 follow-up visits. Patients were classified as stable or exacerbating using a modified Fuch's pulmonary exacerbation score. RESULTS: 226 samples were tested from 111 patients. P. jirovecii was more likely to be detected in samples at acute pulmonary exacerbation (7/76 (9.2%)) compared with stable visits (3/150 (2%)), p = 0.03. P. jirovecii was detected less frequently if patients had received co-trimoxazole within 3 months of sample collection (0% versus 29.7%, p = 0.03). CONCLUSIONS: Prevalence of P. jirovecii in stable patients is low, but P. jirovecii is detected in approximately 1 in 10 patients experiencing an acute pulmonary exacerbation.

An international, multicentre evaluation and description of Burkholderia pseudomallei infection in cystic fibrosis.

BACKGROUND: Several cases of Burkholderia pseudomallei infection in CF have been previously reported. We aimed to identify all cases globally, risk factors for acquisition, clinical consequences, and optimal treatment strategies. METHODS: We performed a literature search to identify all published cases of B. pseudomallei infection in CF. In addition we hand-searched respiratory journals, and contacted experts in infectious diseases and CF around the world. Supervising clinicians for identified cases were contacted and contemporaneous clinical data was requested. RESULTS: 25 culture-confirmed cases were identified. The median age at acquisition was 21 years, mean FEV1 % predicted was 60 %, and mean BMI was 19.5 kg/m(2). The location of acquisition was northern Australia or south-east Asia for most. 19 patients (76 %) developed chronic infection, which was usually associated with clinical decline. Successful eradication strategies included a minimum of two weeks of intravenous ceftazidime, followed by a consolidation phase with trimethoprim/sulfamethoxazole, and this resulted in a higher chance of success when instituted early. Three cases of lung transplantation have been recorded in the setting of chronic B. pseudomallei infection. CONCLUSION: Chronic carriage of B. pseudomallei in patients with CF appears common after infection, in contrast to the non-CF population. This is often associated with an accelerated clinical decline. Lung transplantation has been performed in select cases of chronic B. pseudomallei infection.

Rapid Detection of Emerging Pathogens and Loss of Microbial Diversity Associated with Severe Lung Disease in Cystic Fibrosis.

Respiratory infection in cystic fibrosis (CF) is polymicrobial, but standard sputum microbiology does not account for the lung microbiome or detect changes in microbial diversity associated with disease. As a clinically applicable CF microbiome surveillance scheme, total sputum nucleic acids isolated by a standard high-throughput robotic method for accredited viral diagnosis were profiled for bacterial diversity using ribosomal intergenic spacer analysis (RISA) PCR. Conventional culture and RISA were performed on 200 paired sputum samples from 93 CF adults; pyrosequencing of the 16S rRNA gene was applied to 59 patients to systematically determine bacterial diversity. Compared to the microbiology data, RISA profiles clustered into two groups: the emerging nonfermenting Gram-negative organisms (eNFGN) and Pseudomonas groups. Patients who were culture positive for Burkholderia, Achromobacter, Stenotrophomonas, and Ralstonia clustered within the eNFGN group. Pseudomonas group RISA profiles were associated with Pseudomonas aeruginosa culture-positive patients. Sequence analysis confirmed the abundance of eNFGN genera and Pseudomonas within these respective groups. Low bacterial diversity was associated with severe lung disease (P < 0.001) and the presence of Burkholderia (P < 0.001). An absence of Streptococcus (P < 0.05) occurred in individuals with lung function in the lowest quartile. In summary, nucleic acids isolated from CF sputum can serve as a single template for both molecular virology and bacteriology, with a RISA PCR rapidly detecting the presence of dominant eNFGN pathogens or P. aeruginosa missed by culture (11% of cases). We provide guidance for how this straightforward CF microbiota profiling scheme may be adopted by clinical laboratories.

What is the role of noninvasive ventilation in cystic fibrosis?

PURPOSE OF REVIEW: The use of noninvasive ventilatory support in patients with cystic fibrosis (CF) has increased exponentially over the past 2 decades. This review examines the current knowledge and considers potential future directions for use of noninvasive ventilation in CF patients. RECENT FINDINGS: Noninvasive ventilation was originally reported as a bridge to transplantation in CF patients with severe respiratory failure but is now used as a long-term treatment modality for patients with respiratory failure independent of transplant status. In 2013 to 2014, over 400 publications on noninvasive ventilation demonstrate its increasing clinical application, however only seven reference CF. Recent technological advances and potential benefits to CF patients are considered. SUMMARY: The role of noninvasive ventilation in CF patients in chronic respiratory failure is established, but future prospective studies are needed to determine further indications and optimal timing of this intervention. Developments in both ventilator and interface design may enhance the efficacy of ventilation in CF patients but require careful individualized assessment and regular review. The implications on treatment burden and quality of life in CF also need to be studied.

Incidence and clinical impact of respiratory viruses in adults with cystic fibrosis.

BACKGROUND: Viral respiratory infection (VRI) is a common cause of pulmonary exacerbations in children with cystic fibrosis (CF). The importance of VRI in adult CF populations is unclear. OBJECTIVE: To determine the incidence and clinical impact of VRI among adults with CF. METHODS: One hundred adults with CF were followed up prospectively for 12 months. Sputum, nose swabs and throat swabs were collected every 2 months and at onset of pulmonary exacerbation. PCR assays for adenovirus, influenza A&B, human metapneumovirus, parainfluenza 1-3, respiratory syncytial virus and human rhinovirus were performed on each sample. Symptom scores, spirometry and inflammatory markers were measured at each visit. RESULTS: One or more respiratory viruses were detected in 191/626 (30.5%) visits. Human rhinovirus accounted for 72.5% of viruses. Overall incidence of VRI was 1.66 (95% CI 1.39 to 1.92) cases/patient-year. VRI was associated with increased risk of pulmonary exacerbation (OR=2.19; 95% CI 1.56 to 3.08; p<0.001) and prescription of antibiotics (OR=2.26; 95% CI 1.63 to 3.13; p<0.001). Virus-positive visits were associated with higher respiratory symptom scores and greater C-reactive protein levels. Virus-positive exacerbations had a lower acute fall in FEV1 than virus-negative exacerbations (12.7% vs 15.6%; p=0.040). The incidence of exacerbations, but not VRI, was associated with greater lung function decline over 12 months (-1.79% per pulmonary exacerbation/year; 95% CI -3.4 to -0.23; p=0.025). CONCLUSION: VRI is common in adults with CF and is associated with substantial morbidity. Respiratory viruses are a potential therapeutic target in CF lung disease.

Cerebral air embolism following transbronchial lung biopsy during flexible bronchoscopy.

During a diagnostic flexible bronchoscopy an 84 year old patient suffered a sudden reduction in conscious level following a transbronchial lung biopsy. A subsequent computed tomography brain scan confirmed cerebral air emboli. The patient survived following a period of supportive treatment in the critical care unit. Transbronchial lung biopsy may cause disruption of vessels walls within the lung parenchyma. Increased airway pressure, caused by the patient exhaling against a bronchoscope wedged within a segmental bronchi, may subsequently force air bubbles through the vessel wall defects. This may explain the occurrence of air emboli. This is a rare report of air embolism complicating transbronchial lung biopsy and all bronchoscopists should aware of this potentially fatal complication.

Chronic rhinovirus infection in an adult with cystic fibrosis.

Rhinovirus is a common cause of exacerbations of cystic fibrosis (CF) and is usually considered a self-limiting infection. We report a case of chronic infection with rhinovirus A type 33 in a 43-year-old male with CF which has persisted for over 2 years.

Is hydrogen cyanide a marker of Burkholderia cepacia complex?

Biofilm cultures of Burkholderia cepacia complex (BCC) infection have been found to generate the nonvolatile cyanide ion. We investigated if gaseous hydrogen cyanide (HCN) was a marker of BCC infection. Selected ion flow tube mass spectrometry analysis showed HCN was not elevated in the headspace of planktonic or biofilm cultures or in the exhaled breath of adult cystic fibrosis patients with chronic BCC infection. HCN is therefore not an in vitro or in vivo marker of BCC.