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.

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.

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.

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.

Hydrogen cyanide concentrations in the breath of adult cystic fibrosis patients with and without Pseudomonas aeruginosa infection.

Elevated concentrations of hydrogen cyanide (HCN) have been detected in the headspace of Pseudomonas aeruginosa (PA) cultures and in the breath of children with cystic fibrosis (CF) and PA infection. The use of mouth-exhaled breath HCN as a marker of PA infection in adults is more difficult to assess as some without PA infection generate HCN in their mouths. The analysis of breath exhaled via the nose, thereby avoiding volatile compounds produced in the mouth, will demonstrate elevated concentrations of HCN in adult CF patients chronically infected with PA. Using selected ion flow mass spectrometry (SIFT-MS), the mouth and the nose-exhaled breaths of 20 adult CF patients; 10 with chronic PA infection and 10 free from PA infection, were analysed for HCN. Acetone and ethanol were also measured as controls. SIFT-MS allows direct sampling and analysis of single breath exhalations, obviating the need to collect samples into bags or onto traps, which can compromise samples. HCN was detected in the mouth-exhaled breath of patients in both groups and in the nose-exhaled breath of patients with chronic PA infection. The difference in median (IQR) nose-exhaled HCN between the groups is statistically significant (11 (0.8-18) ppbv versus 0 (0-3.2) ppbv, p = 0.03). The concentrations of acetone and ethanol in nose-exhaled and mouth-exhaled breath are in keeping with previous studies. HCN in nose-exhaled breath is a biomarker of chronic airway infection with PA in adults with CF. Its application as a non-invasive diagnostic test for early PA infection warrants further investigation.

Itraconazole and inhaled fluticasone causing hypothalamic-pituitary-adrenal axis suppression in adults with cystic fibrosis.

BACKGROUND: Although there have been case reports of hypothalamic-pituitary-adrenal (HPA) axis suppression in patients with cystic fibrosis (CF) caused by the combination of oral itraconazole and inhaled fluticasone, to date no study has assessed the incidence of this potentially serious side effect. METHODS: Synacthen tests were conducted on all patients with CF receiving itraconazole and inhaled fluticasone and an equal number of patients with CF receiving inhaled fluticasone but not itraconazole. Itraconazole levels were measured in patients receiving the therapy. RESULTS: Twelve patients receiving itraconazole and fluticasone underwent synacthen tests. All 12 had abnormal synacthen test results and 10/12 (83%) had HPA axis suppression. Two patients had severe HPA axis suppression with a peak cortisol <75 nmol/L and further 3 patients had moderately severe suppression with a peak cortisol <250 nmol/L. In contrast, only 2/12 on fluticasone alone had HPA axis suppression (both mild). The median (range) basal cortisol levels were significantly lower in those patients receiving itraconazole and inhaled fluticasone compared to those on fluticasone alone (219(22-508)nmol/L v 348(41-738)nnmol/L, p=0.02), similar results were seen for peak cortisol levels (404(59-706)nmol/L v 672(432-1178)nmol/L, p<0.001) and cortisol rise (179(37-240)nmol/L v 368(210-539)nmol/L, p<0.001). The median (range) itraconazole level was 5.5(1.7-14.7)mg/L. Neither itraconazole levels nor fluticasone dose correlated with the degree of adrenal suppression. CONCLUSIONS: In this study, all patients receiving itraconazole and inhaled fluticasone had abnormal synacthen test results. The incidence of HPA axis suppression with this treatment combination appears to be higher than that previously reported with itraconazole and inhaled budesonide.

Aspergillus bronchitis without significant immunocompromise.

Aspergillus bronchitis is poorly understood and described. We extracted clinical data from more than 400 referred patients with persistent chest symptoms who did not fulfill criteria for allergic, chronic, or invasive aspergillosis. Symptomatic patients with a positive culture or real-time PCR for Aspergillus spp. were reviewed. Seventeen patients fulfilled the selected criteria. Fourteen were women, with a mean age of 57 years (range 39-76). Sixteen of the patients had productive cough, eight had voluminous tenacious sputum, and seven had recurrent chest infections. Eight patients had Medical Research Council dyspnea scores of 4-5; 12 had bronchiectasis; and 13 patients grew A. fumigatus, 3 A. niger, and 1 A. terreus. Twelve of the 17 patients (71%) had elevated Aspergillus IgG (47-137 mg/L, mean 89.2) and 5 (29%) had elevated Aspergillus precipitins. Six of 12 (50%) had a major response to antifungal therapy and five of 12 (42%) patients relapsed, requiring long-term therapy. Aspergillus bronchitis is a discrete clinical entity in patients with structural lung disease but who are not significantly immunocompromised. It is distinct from asymptomatic fungal colonization and other forms of aspergillosis, and may respond to antifungal therapy.

A therapeutic conundrum: recurrent cystic-fibrosis-related haemoptysis complicated by acute pulmonary embolism.

The authors present the case of an older patient with cystic fibrosis (CF) and recurrent haemoptysis complicated by acute pulmonary embolism. The patient was treated successfully with a combination of anticoagulation and bronchial artery embolisation. The management of CF-related haemoptysis, the impact of an ageing CF population and the incidence of thromboembolic disease in CF are discussed.

Pulmonary artery pressure in cystic fibrosis adults: characteristics, clinical correlates and long-term follow-up.

BACKGROUND: We examined pulmonary artery pressure (PAP) characteristics of CF adults, studied clinical correlates and long-term survival. METHODS: Comprehensive clinical data were collected and Doppler echocardiography was used to estimate PAP in 109 stable CF adults and 50 healthy controls. RESULTS: CF patients had lower day and night-time oxygen status, elevated CRP and BNP, and elevated PAP (27.7(13.2, 62.8) mmHg patients v 17.9(11.3, 30.9) mmHg controls, p<0.001). Even patients with mild pulmonary disease had raised PAP. PAP measurements strongly correlated with arterial partial pressure of oxygen (PaO(2), r=-0.673, p<0.001), and FEV(1) percentage predicted (FEV(1)%, r=-0.642, p<0.001) which were both independent predictors of PAP. At 10 year follow up PAP measurements were related to survival but FEV(1)% and PaO(2) were both stronger predictors of death. CONCLUSIONS: PAP is raised in CF adults and correlates with pulmonary disease severity. Unlike PaO(2) and FEV(1)%, it does not appear to be an independent prognostic marker.

Successful treatment of cepacia syndrome with a combination of intravenous cyclosporin, antibiotics and oral corticosteroids.

Burkholderia cepacia complex (BCC) is a group of 17 closely related bacterial species that can cause pulmonary infection in patients with cystic fibrosis (CF). The clinical manifestations of BCC infection are varied but can include cepacia syndrome, which is a rapidly progressing necrotising pneumonia with an almost universally fatal outcome. We report the case of a 38 year old man, known to have chronic infection with the ET12 strain of Burkholderia cenocepacia who developed cepacia syndrome 26 years after initial infection. Aggressive treatment with a combination of 4 intravenous antibiotics, oral corticosteroids and cyclosporin brought about clinical, radiological and biochemical resolution of his cepacia syndrome. This case highlights the possible role of cyclosporin in the treatment of cepacia syndrome.