Understanding Pseudomonas status among adults with cystic fibrosis: a real-world comparison of the Leeds criteria against clinicians' decision.

Pseudomonas aeruginosa status influences cystic fibrosis (CF) clinical management but no 'gold standard' definition exists. The Leeds criteria are commonly used but may lack sensitivity for chronic P. aeruginosa. We compared clinicians' decision with the Leeds criteria in three adult CF centres. Two independent prospective datasets (Sheffield dataset, n = 185 adults; ACtiF pilot dataset, n = 62 adults from two different centres) were analysed. Clinicians involved in deciding P. aeruginosa status were blinded to the study objectives. Clinicians considered more adults with CF to have chronic P. aeruginosa infection compared to the Leeds criteria. This was more so for the Sheffield dataset (106/185, 57.3% with clinicians' decision vs. 80/185, 43.2% with the Leeds criteria; kappa coefficient between these two methods 0.72) compared to the ACtiF pilot dataset (34/62, 54.8% with clinicians' decision vs. 30/62, 48.4% with the Leeds criteria; kappa coefficient between these two methods 0.82). However, clinicians across different centres were relatively consistent once age and severity of lung disease, as indicated by the type of respiratory samples provided, were taken into account. Agreement in P. aeruginosa status was similar for both datasets among adults who predominantly provided sputum samples (kappa coefficient 0.78) or adults > 25 years old (kappa coefficient 0.82). Across three different centres, clinicians did not always agree with the Leeds criteria and tended to consider the Leeds criteria to lack sensitivity. Where disagreement occurred, clinicians tended to diagnose chronic P. aeruginosa infection because other relevant information was considered. These results suggest that a better definition for chronic P. aeruginosa might be developed by using consensus methods to move beyond a definition wholly dependent on standard microbiological results.

Rescue therapy within the UK Cystic Fibrosis Registry: An exploration of predictors of intravenous antibiotic use amongst adults with CF.

BACKGROUND AND OBJECTIVE: Intravenous (i.v.) antibiotics are needed for rescue when preventative therapy fails to achieve stability among adults with cystic fibrosis (CF). Understanding the distribution of i.v. days can provide insight into the care that adults with CF need. We aim to determine the baseline characteristics that are associated with higher i.v. use, in particular to test the hypothesis that prior-year i.v. use is associated with future-year i.v. use. METHODS: This is a cross-sectional analysis of the 2013-2014 UK CF registry data. Stepwise logistic regression was performed using current-year i.v. days as the dependent variable, and demographic variables including prior-year i.v. days as the covariates. Based on these results, study sample was divided into clinically meaningful subgroups using analysis similar to tree-based method. RESULTS: Data were available for 4269 adults in 2013 and 4644 adults in 2014. Prior-year i.v. use was the strongest predictor for current-year i.v. use followed by forced expiratory volume in 1 s (FEV1 ). Adults with high prior-year i.v. use (>14 days) continued to require high levels of i.v., regardless of FEV1 . Those with high prior-year i.v. use and FEV1 ≥70% had higher current-year i.v. days compared to adults with low prior-year i.v. use and FEV1 <40% (28 days, interquartile range (IQR): 11-41 days vs 14 days, IQR: 0-28 days; Mann-Whitney P-value <0.001 in 2013). CONCLUSION: CF people with prior high levels of rescue often continue to need high levels of rescue even if they have good FEV1 . The reasons for this require further investigations.

Prospectively predicting Pseudomonas aeruginosa infection/s using routine data from the UK cystic fibrosis register.

RATIONALE AND AIMS: Lung health of people with cystic fibrosis (PwCF) can be preserved by daily use of inhaled therapy. Adherence to inhaled therapy, therefore, provides an important process measure to understand the success of care and can be used as a quality indicator. Defining adherence is problematic, however, since the number of prescribed treatments varies considerably between PwCF. The problem is less pronounced among those with Pseudomonas aeruginosa (PA), for whom at least three daily doses of nebulized therapy should be prescribed and who thus constitute a more homogeneous group. The UK CF Registry provides routine data on PA status, but data are only available 12 months after collection. In this study, we aim to prospectively identify contemporary PA status from historic registry data. METHOD: UK CF Registry data from 2011 to 2015 for PwCF aged ≥16 was used to determine a pragmatic prediction rule for identifying contemporary PA status using historic registry data. Accuracy of three different prediction rules was assessed using the positive predictive value (PPV). The number and proportion of adults predicted to have PA infection were determined overall and per center for the selected prediction rule. Known characteristics linked to PA status were explored to ensure the robustness of the prediction rule. RESULTS: Having CF Registry defined chronic PA status in the two previous years is the selected definition to predict a patient will have PA infection within the current year (population-level PPV = 96%-97%, centre level PPV = 85%-100%). This approach provides a subset of data between 1852 and 1872 patients overall and a range of 8 to 279 patients per center. CONCLUSION: Historic registry data can be used to contemporaneously identify a subgroup of patients with chronic PA. Since this patient group has a narrower treatment schedule, this can facilitate a better benchmarking of adherence across centers.

A comparison of the CFHH criteria against the Leeds criteria in determining the Pseudomonas aeruginosa status among adults with cystic fibrosis.

BACKGROUND: Pseudomonas aeruginosa (PA) status influences management decisions in cystic fibrosis (CF) but diagnostic approaches vary. We evaluated the ability of the CFHealthHub (CFHH) criteria, which consist of two major and four minor statements, in diagnosing chronic PA infection among adults with CF. METHODS: In this retrospective cross-sectional analysis, we compared the CFHH criteria against the Leeds criteria. Data were collected between 1st January and 31st December 2016 from all adults with CF receiving care at Sheffield, excluding those with lung transplantation (n = 7) or on ivacaftor (n = 13). The CFHH criteria PA status were cross-tabulated against the Leeds criteria, and clinical outcomes between chronic PA vs non chronic PA for both criteria were compared. RESULTS: This analysis included 186 adults with CF (90 females, median age 27 years, median baseline FEV1 78.5%). The CFHH criteria diagnosed more cases of chronic PA (116/186, 62.4% vs 79/186, 42.5%), and 37/107 cases of non-chronic PA according to the Leeds criteria were deemed chronic PA by the CFHH criteria. The magnitude of difference in %FEV1 decline between chronic PA vs non chronic PA was slightly greater for the CFHH criteria (-0.6%, 95% CI -1.8 to 0.6%) compared to the Leeds criteria (-0.2%, 95% CI -1.3 to 1.0%). CONCLUSIONS: The CFHH criteria detected more chronic PA cases yet still retained similar levels of discrimination for health outcomes in comparison to the Leeds criteria. These findings provide preliminary evidence for the validity of the CFHH criteria among adults with CF.

Exploring the implications of different approaches to estimate centre-level adherence using objective adherence data in an adult cystic fibrosis centre - a retrospective observational study.

BACKGROUND: Accurate centre-level medication adherence measurement allows identification of highly performing CF centres, drives shared learning and informs quality improvement. Self-reported adherence is unreliable but data-logging nebulisers can capture objective data. However, adherence levels in current literature are limited by the use of agreed prescriptions and convenience sampling. In this single-centre retrospective study, we quantified the differences in centre-level adherence with different methods of calculating adherence (unadjusted vs normative adherence) and different data sampling frames (convenience sampling vs including difficult to obtain data). METHODS: Adherence data were objectively captured using I-neb® from 2013-2016 in Sheffield Adult CF Centre. Adults on non data-logging devices, on ivacaftor or with previous lung transplantation were excluded. Adherence was calculated based on agreed regimen ('unadjusted adherence') or minimum required regimen ('normative adherence'). I-nebs® not brought to clinic were downloaded during home visits. Adults not on any inhaled therapy but with chronic Pseudomonas aeruginosa infection were included by counting their adherence as "0". RESULTS: Of the 131 included adults, 126 provided I-neb® data. Calculating unadjusted adherence from I-nebs® brought to clinics resulted in the highest centre-level adherence (median 41.8% in 2013). Median adherence reduced after sequentially accounting for minimum required regimen (40.0% in 2013), I-nebs® not brought to clinics (32.9% in 2013) and adults not on any inhaled therapy (31.0% in 2013). CONCLUSIONS: Different approaches of calculating adherence produced different adherence levels. Adherence levels based only on agreed regimen among adults who readily brought their nebulisers to clinics can over-estimate the effective adherence of CF centres.

Intravenous antibiotic use and exacerbation events in an adult cystic fibrosis centre: A prospective observational study.

INTRODUCTION: In CF, people with higher FEV1 are less aggressively treated with intravenous (IV) antibiotics, with resultant negative impact on their health outcomes. This could be entirely clinician-driven, but patient choice may also influence IV use. In this prospective observational study, we explored IV recommendations by clinicians and IV acceptance by adults with CF to understand how clinical presentations consistent with exacerbations resulted in IV use. METHODS: Clinical presentations consistent with exacerbations, IV recommendation by clinicians and IV acceptance by patients were prospectively identified for every adult with CF in Sheffield throughout 2016, excluding those who had lung transplantation (n = 7) or on ivacaftor (n = 13). Relevant demographic data, e.g. %FEV1, were extracted from medical records. Multi-level mixed-effects logistic regression models were used to compare IV recommendations vs non-recommendations for all clinical encounters, and IV acceptance vs non-acceptance for all IV recommendations. RESULTS: Among 186 adults (median age 27 years, median FEV1 78.5%), there were 434 exacerbation events and 318 IV use episodes following 1010 clinical encounters. Only 254 (58.5%) of exacerbations were IV treated. A diagnosis of exacerbation, higher number of symptoms and lower %FEV1 were independent predictors for IV recommendation by clinicians. Higher number of symptoms and lower %FEV1 were also independent predictors for IV acceptance by adults with CF. CONCLUSIONS: Lower IV use among adults with higher %FEV1 was influenced by both clinicians' and patients' decisions. Using IV antibiotics as an exacerbation surrogate could under-estimate exacerbation rates and conceal differential treatment decisions according to varying clinical characteristics.

Using different methods to process forced expiratory volume in one second (FEV 1) data can impact on the interpretation of FEV 1 as an outcome measure to understand the performance of an adult cystic fibrosis centre: A retrospective chart review.

Background: Forced expiratory volume in one second (FEV 1) is an important cystic fibrosis (CF) prognostic marker and an established endpoint for CF clinical trials. FEV 1 is also used in observation studies, e.g. to compare different centre's outcomes. We wished to evaluate whether different methods of processing FEV 1 data can impact on centre outcome. Methods: This is a single-centre retrospective analysis of routinely collected data from 2013-2016 among 208 adults. Year-to-year %FEV 1 change was calculated by subtracting best %FEV 1 at Year 1 from Year 2 (i.e. negative values indicate fall in %FEV 1), and compared using Friedman test. Three methods were used to process %FEV 1 data. First, %FEV 1 calculated with Knudson equation was extracted directly from spirometer machines. Second, FEV 1 volume were extracted then converted to %FEV 1 using clean height data and Knudson equation. Third, FEV 1 volume were extracted then converted to %FEV 1 using clean height data and GLI equation. In addition, year-to-year variation in %FEV 1 calculated using GLI equation was adjusted for baseline %FEV 1 to understand the impact of case-mix adjustment. Results: Year-to-year fall in %FEV 1 reduced with all three data processing methods but the magnitude of this change differed. Median change in %FEV 1 for 2013-2014, 2014-2015 and 2015-2016 was -2.0, -1.0 and 0.0 respectively using %FEV 1 in Knudson equation whereas the median change was -1.1, -0.9 and -0.3 respectively using %FEV 1 in the GLI equation. A statistically significant p-value (0.016) was only obtained when using %FEV 1 in Knudson equation extracted directly from spirometer machines. Conclusions: Although the trend of reduced year-to-year fall in %FEV 1 was robust, different data processing methods yielded varying results when year-to-year variation in %FEV 1 was compared using a standard related group non-parametric statistical test. Observational studies with year-to-year variation in %FEV 1 as an outcome measure should carefully consider and clearly specify the data processing methods used.

Do cystic fibrosis centres with the lowest FEV1 still use the least amount of intravenous antibiotics? A registry-based comparison of intravenous antibiotic use among adult CF centres in the UK.

BACKGROUND: The Epidemiologic Study of Cystic Fibrosis using 1995-1996 and 2003-2005 data found that CF centres with lowest FEV1 tended to use fewer intravenous antibiotics. We repeated the analyses using 2013-2014 UK CF registry data to determine if this was still the case. METHODS: Analysing data for 2013 and 2014 separately, 28 adult CF centres were ranked according to median % age-adjusted FEV1. The top 7 centres were placed in the 'upper quarter' (best FEV1), the bottom 7 centres in 'lower quarter' (lowest FEV1), and the rest in 'middle half'. IV use was stratified according to %FEV1, then compared between the three groups. RESULTS: Centres in the 'upper quarter' and 'middle half' used significantly more IV antibiotics compared to centres in the 'lower quarter' (van Elteren test P-value<0.001). Regression analyses showed that people with CF attending centres in the 'upper quarter' or 'middle half' are 30-50% more likely to receive at least one IV course per year compared to people attending centres in the 'lower quarter'. CONCLUSIONS: CF centres with lowest FEV1 are still distinguished by lower use of intravenous antibiotics.

The importance of data issues when comparing cystic fibrosis registry outcomes between countries: Are annual review FEV1 in the UK only collected when subjects are well?

RATIONALE, AIMS AND OBJECTIVE: Cross-country comparisons of cystic fibrosis (CF) outcomes can potentially identify variation in care but are dependent on data quality. An important assumption is that the UK annual review FEV1 is only collected during periods of clinical stability. If this assumption does not hold, results of FEV1 comparisons may be biased in favour of registries with encounter-based FEV1 . We aimed to test the assumption that CF annual reviews in the UK are only performed during periods of clinical stability. METHOD: Prospective encounter-based data collected in Sheffield (n = 174) was used to establish whether annual review FEV1 were always collected during periods of clinical stability and to determine the group-level discrepancy between annual review vs best FEV1 . We then went on to quantify the group-level discrepancy between annual review and best annual FEV1 readings within the UK registry (n = 2995) to determine if the differences observed in Sheffield also apply to the wider UK data. RESULTS: Sheffield results showed a group-level discrepancy between best and annual review FEV1 of -2.5% (95% CI -3.95% to -1.2%) for annual reviews performed during periods of clinical stability (n = 50). The group-level discrepancy is larger at -8.0% (95% CI -11.2% to -4.9%) among annual reviews performed during periods of clinical instability (n = 13). Therefore, the magnitude of this group-level discrepancy is a surrogate for the proportion of clinically stable annual reviews-smaller discrepancy indicates a higher proportion of clinically stable annual reviews and vice versa. The overall group-level discrepancy in the UK registry (-5.6%, 95% CI -5.9 to -5.4%) was similar to Sheffield (-6.1%, 95% CI -7.1 to -5.1%). Around 20% of the clinician reviewed, annual reviews in Sheffield were performed during periods of clinically instability. CONCLUSIONS: Annual review FEV1 underestimates lung health of adults with CF in the UK and may bias cross-country comparisons.

Case Report: Dual nebulised antibiotics among adults with cystic fibrosis and chronic Pseudomonas infection.

Pulmonary exacerbations in adults with cystic fibrosis (CF) and chronic Pseudomonas aeruginosa (Psae) infection are usually treated with dual intravenous antibiotics for 14 days, despite the lack of evidence for best practice. Intravenous antibiotics are commonly associated with various systemic adverse effects, including renal failure and ototoxicity. Inhaled antibiotics are less likely to cause systematic adverse effects, yet can achieve airway concentrations well above conventional minimum inhibitory concentrations. Typically one inhaled antibiotic is used at a time, but dual inhaled antibiotics (i.e. concomitant use of two different inhaled antibiotics) may have synergistic effect and achieve better results in the treatment of exacerbations. We presented anecdotal evidence for the use of dual inhaled antibiotics as an acute treatment for exacerbations, in the form of a case report. A female in her early thirties with CF and chronic Psae infection improved her FEV 1 by 5% and 2% with two courses of dual inhaled antibiotics to treat exacerbations in 2016. In contrast, her FEV 1 changed by 2%, -2%, 0% and 2%, respectively, with four courses of dual intravenous antibiotics in 2016. Baseline FEV 1 was similar prior to all six courses of treatments. The greater FEV 1 improvements with dual inhaled antibiotics compared to dual intravenous antibiotics suggest the potential role of using dual inhaled antibiotics to treat exacerbations among adults with CF and chronic Psae infection, especially since a greater choice of inhaled anti-pseudomonal antibiotics is now available. A previous study in 1985 has looked at the concomitant administration of inhaled tobramycin and carbenicillin, by reconstituting antibiotics designed for parenteral administration. To our knowledge, this is the first literature to describe the concomitant use of two different antibiotics specifically developed for delivery via the inhaled route.

An empirical method to cluster objective nebulizer adherence data among adults with cystic fibrosis.

BACKGROUND: The purpose of using preventative inhaled treatments in cystic fibrosis is to improve health outcomes. Therefore, understanding the relationship between adherence to treatment and health outcome is crucial. Temporal variability, as well as absolute magnitude of adherence affects health outcomes, and there is likely to be a threshold effect in the relationship between adherence and outcomes. We therefore propose a pragmatic algorithm-based clustering method of objective nebulizer adherence data to better understand this relationship, and potentially, to guide clinical decisions. METHODS TO CLUSTER ADHERENCE DATA: This clustering method consists of three related steps. The first step is to split adherence data for the previous 12 months into four 3-monthly sections. The second step is to calculate mean adherence for each section and to score the section based on mean adherence. The third step is to aggregate the individual scores to determine the final cluster ("cluster 1" = very low adherence; "cluster 2" = low adherence; "cluster 3" = moderate adherence; "cluster 4" = high adherence), and taking into account adherence trend as represented by sequential individual scores. The individual scores should be displayed along with the final cluster for clinicians to fully understand the adherence data. THREE ILLUSTRATIVE CASES: We present three cases to illustrate the use of the proposed clustering method. CONCLUSION: This pragmatic clustering method can deal with adherence data of variable duration (ie, can be used even if 12 months' worth of data are unavailable) and can cluster adherence data in real time. Empirical support for some of the clustering parameters is not yet available, but the suggested classifications provide a structure to investigate parameters in future prospective datasets in which there are accurate measurements of nebulizer adherence and health outcomes.

Accurate reporting of adherence to inhaled therapies in adults with cystic fibrosis: methods to calculate "normative adherence".

BACKGROUND: Preventative inhaled treatments in cystic fibrosis will only be effective in maintaining lung health if used appropriately. An accurate adherence index should therefore reflect treatment effectiveness, but the standard method of reporting adherence, that is, as a percentage of the agreed regimen between clinicians and people with cystic fibrosis, does not account for the appropriateness of the treatment regimen. We describe two different indices of inhaled therapy adherence for adults with cystic fibrosis which take into account effectiveness, that is, "simple" and "sophisticated" normative adherence. METHODS TO CALCULATE NORMATIVE ADHERENCE: Denominator adjustment involves fixing a minimum appropriate value based on the recommended therapy given a person's characteristics. For simple normative adherence, the denominator is determined by the person's Pseudomonas status. For sophisticated normative adherence, the denominator is determined by the person's Pseudomonas status and history of pulmonary exacerbations over the previous year. Numerator adjustment involves capping the daily maximum inhaled therapy use at 100% so that medication overuse does not artificially inflate the adherence level. THREE ILLUSTRATIVE CASES: Case A is an example of inhaled therapy under prescription based on Pseudomonas status resulting in lower simple normative adherence compared to unadjusted adherence. Case B is an example of inhaled therapy under-prescription based on previous exacerbation history resulting in lower sophisticated normative adherence compared to unadjusted adherence and simple normative adherence. Case C is an example of nebulizer overuse exaggerating the magnitude of unadjusted adherence. CONCLUSION: Different methods of reporting adherence can result in different magnitudes of adherence. We have proposed two methods of standardizing the calculation of adherence which should better reflect treatment effectiveness. The value of these indices can be tested empirically in clinical trials in which there is careful definition of treatment regimens related to key patient characteristics, alongside accurate measurement of health outcomes.

Promoting adherence to nebulized therapy in cystic fibrosis: poster development and a qualitative exploration of adherence.

BACKGROUND: Cystic fibrosis (CF) health care professionals recognize the need to motivate people with CF to adhere to nebulizer treatments, yet little is known about how best to achieve this. We aimed to produce motivational posters to support nebulizer adherence by using social marketing involving people with CF in the development of those posters. METHODS: The Sheffield CF multidisciplinary team produced preliminary ideas that were elaborated upon with semi-structured interviews among people with CF to explore barriers and facilitators to the use of nebulized therapy. Initial themes and poster designs were refined using an online focus group to finalize the poster designs. RESULTS: People with CF preferred aspirational posters describing what could be achieved through adherence in contrast to posters that highlighted the adverse consequences of nonadherence. A total of 14 posters were produced through this process. CONCLUSION: People with CF can be engaged to develop promotional material to support adherence, providing a unique perspective differing from that of the CF multidisciplinary team. Further research is needed to evaluate the effectiveness of these posters to support nebulizer adherence.

A case report of a salivary amylase secreting plasmacytoma in a patient with multiple myeloma.

A 70-year-old lady with a past medical history of light chain myeloma, chronic renal failure and a left breast plasmacytoma treated with radiotherapy was admitted for drainage of a subsequent left pleural effusion. She was given high dose steroids for her myeloma, following which she developed abdominal pain suspicious of pancreatitis. Results revealed a raised serum amylase of 5117, a modified Glasgow score of 3 and normal calcium levels. The working diagnosis was drug-induced pancreatitis and steroids were stopped. She remained well and her abdominal pain settled, but amylase remained markedly raised despite no findings of pancreatic pathology. A subsequent isoenzyme test on the amylase found it to be salivary amylase secreted from the plasmacytoma. The patient had her steroid therapy restarted and was allowed to be discharged from hospital.