Diagnosing Cystic Fibrosis in Adults.

Diagnosing cystic fibrosis (CF) in adulthood is not a rare occurrence for CF centers despite the popular belief that the diagnosis is achieved almost universally in childhood by means of newborn screening or early clinical presentation. The purpose of this review article is to highlight specific considerations of adult diagnosis of CF. Obtaining a diagnosis of CF at any age is exceptionally important to ensure optimal treatment, monitoring, and support. In the new era of more personalized treatment with the advent of transformative therapies targeting the underlying protein defect, accurate diagnosis is of increasing importance. This review highlights the diagnostic algorithm leading to a new diagnosis of CF in adults. The diagnosis is usually confirmed in the presence of a compatible clinical presentation, evidence of cystic fibrosis transmembrane conductance regulator (CFTR) protein dysfunction, and/or identification of variants in the CFTR gene believed to alter protein function. Achieving the diagnosis, however, is not always straightforward as CFTR protein function exists on a continuum with different organs displaying varying sensitivity to diminution in function. We highlight the current knowledge regarding the epidemiology of CF diagnosed in adults and outline the various clinical presentations, including pulmonary and extrapulmonary, which are more common in this population. We expand on the stepwise testing procedures that lead to diagnosis, paying particular attention to additional levels of testing which may be required to achieve an accurate diagnosis. There continues to be an important need for both pulmonary and other specialists to be aware of the potential for later presentation of CF, as the improvements in treatment over decades have had large positive impacts on prognosis for people with this condition.

Mediation of the total effect of cystic fibrosis-related diabetes on mortality: A UK Cystic Fibrosis Registry cohort study.

AIM: To investigate whether the effect of cystic fibrosis-related diabetes (CFRD) on the composite outcome of mortality or transplant could act through lung function, pulmonary exacerbations and/or nutritional status. METHODS: A retrospective cohort of adult cystic fibrosis (CF) patients who had not been diagnosed with CFRD were identified from the UK Cystic Fibrosis Registry (n = 2750). Rate of death or transplant was compared between patients who did and did not develop CFRD (with insulin use) during follow-up using Poisson regression, separately by sex. Causal mediation methods were used to investigate whether lung function, pulmonary exacerbations and nutritional status lie on the causal pathway between insulin-treated CFRD and mortality/transplant. RESULTS: At all ages, the mortality/transplant rate was higher in both men and women diagnosed with CFRD. Pulmonary exacerbations were the strongest mediator of the effect of CFRD on mortality/transplant, with an estimated 15% [95% CI: 7%, 28%] of the effect at 2 years post-CFRD diagnosis attributed to exacerbations, growing to 24% [95% CI: 9%, 46%] at 4 years post-diagnosis. Neither lung function nor nutritional status were found to be significant mediators of this effect. Estimates were similar but with wider confidence intervals in a cohort that additionally included people with CFRD but not using insulin. CONCLUSION: There is evidence that pulmonary exacerbations mediate the effect of CFRD on mortality but, as they are estimated to mediate less than one-quarter of the total effect, the mechanism through which CFRD influences survival may involve other factors.

Assessing the health risk of living near composting facilities on lung health, fungal and bacterial disease in cystic fibrosis: a UK CF Registry study.

AIM: To explore the health risk of living near permitted composting sites (PCSs) on disease severity in children and adults with cystic fibrosis (CF) across the UK.  METHODS: A semi-individual cross-sectional study was used to examine the risk of disease severity in people with CF (pwCF) within and beyond 4 km of PCSs in the UK in 2016. All pwCF registered in the UK CF Registry were eligible for this study. Linear and Poisson regressions, adjusted for age, gender, genotype, BMI, Pseudomonas aeruginosa and deprivation, were used to quantify associations between distance to a PCS and percent predicted forced expiratory volume in one second (ppFEV1), pulmonary exacerbations (#IVdays), and fungal and bacterial infections. RESULTS: The mean age of the 9,361 pwCF (3,931 children and 5,430 adults) studied was 20.1 (SD = 14.1) years; 53.3% were male; and 49.2% were homozygous F508del. Over 10% of pwCF (n = 1,015) lived within 4 km of a PCS. We found no statistically significant difference in ppFEV1 and #IVdays/year in children. However, in adults, ppFEV1 was -1.07% lower (95% confidence interval (CI): -2.29%, 0.16%) and #IVdays/year were 1.02 day higher (95%CI: 1.01, 1.04) within 4 km of a PCS. Furthermore, there were statistically significant differences in mean ppFEV1 in CF adults with Aspergillus fumigatus (58.2.% vs 62.0%, p = 0.005) and Candida spp. (56.9% vs 59.9%, p = 0.029) residing within 4 km of a PCS. No associations were identified for allergic bronchopulmonary aspergillosis, P. aeruginosa or Staphylococcus aureus. CONCLUSIONS: This novel national study provides evidence that adults with CF living near a PCS may experience small reductions in lung function, an increased risk of pulmonary exacerbations, and more frequent fungal infections. If confirmed by studies using refined exposure assessment methods accounting for bioaerosol dispersion, these results could have important implications for the living environment of pwCF.

Clinical characteristics and outcomes in adult cystic fibrosis patients with severe lung disease in Porto Alegre, southern Brazil.

BACKGROUND: Advanced lung disease in adult cystic fibrosis (CF) drives most clinical care requirements. The aim was to evaluate outcome (time to death while in the study) in a cohort of adult CF patients with severe lung disease, and to determine the association among baseline patient characteristics and outcome. METHODS: A retrospective cohort study was performed and clinical records between 2000 and 2015 were reviewed. Severe lung disease was defined as forced expiratory volume in the first second (FEV1) < 30% of predicted. Outcomes of all patients, including their date of death or transplantation, were determined till January 1st, 2016. Clinical data were recorded at the entry date. RESULTS: Among 39 subjects included in the study, 20 (51.3%) died, 16 (41.0%) underwent bilateral lung transplantation, and 3 were alive at the end of the study period. Two variables were independently associated with death: body mass index (BMI ≥ 18.5 kg/m2) (HR = 0.78, 95% CI = 0.64-0.96 and p = 0.017) and use of tobramycin inhalation therapy (HR = 3.82, 95% CI = 1.38-10.6 and p = 0.010). Median survival was 37 (95% CI = 16.4-57.6) months. The best cut-off point for BMI was 18.5 kg/m2. Median survival in patients with BMI < 18.5 kg/m2 was 36 months (95% CI = 18.7-53.3). CONCLUSION: Median survival of CF subjects with FEV1 < 30% was 37 months. BMI and tobramycin inhalation therapy were independently associated with death. Median survival in patients with BMI < 18.5 kg/m2 was significantly lower than in patients with BMI ≥ 18.5 kg/m2. The association of tobramycin inhalation with death was interpreted as confounding by severity (use was reserved for advanced lung disease).

New strategies of physical activity assessment in cystic fibrosis: a pilot study.

BACKGROUND: Regular physical activity (PA) is a valued part of cystic fibrosis (CF) care. Although the accelerometer, SenseWear Armband (SWA), accurately measures habitual PA in CF, it is mostly used for research purposes. For the first time, we analyzed different methods of measuring PA in daily life by the use of smartphones and other electronic devices such as smartwatch and Fitbit. METHODS: Twenty-four stable adults with CF (mean age 37.5 ± 11.5SD yrs.; FEV1 58 ± 19% predicted, BMI 22.9 ± 3.2) were studied. Daily PA was monitored for seven consecutive days. All patients wore the accelerometer SWA and at the same time they monitored PA with the electronic device they used routinely. They were allocated into one of four arms according to their device: Smartwatch, Fitbit, Android smartphones and iOS smartphones. PA related measurements included: duration of PA, energy expenditure, number of steps. RESULTS: There was a good agreement between SWA and Fitbit for number of steps (p = 0.605) and energy expenditure (p = 0.143). iOS smartphones were similar to SWA in monitoring the number of steps (p = 0.911). Significant differences were found between SWA and both Smartwatch and Android smartphones. CONCLUSIONS: Fitbit and iOS smartphones seem to be a valuable approach to monitor daily PA. They provide a good performance to measure step number compared to SWA.

"Fortunate are those who take the first steps"? The psychosocial impact of novel drug development.

Novel drug development offers people with cystic fibrosis exciting opportunities but is not without challenges. Currently, there is an understandable emphasis on protecting patients' physical health when developing treatments. However, there appears to be little consideration of how novel drug development impacts on psychosocial wellbeing, or the downstream consequences of this. Using an illustrative case and reviewing the literature we explore themes regarding the psychosocial impact of trial participation and novel drug development and identify areas requiring further research. Through this, we hope to prepare healthcare professionals to better understand the needs of their patients in this rapidly evolving landscape.

Clostridium difficile and cystic fibrosis: management strategies and the role of faecal transplantation.

Clostridium difficile is a bacterial infection that colonises the gut in susceptible hosts. It is associated with exposure to healthcare settings and antibiotic use. It could be assumed that cystic fibrosis (CF) patients are a high-risk group for C.difficile. However, despite high carriage rates, CF patients have low rates of active disease. There are guidelines for the treatment of C.difficile, however little is published specific to treating C.difficile in CF. This article provides an overview of the current management strategies for C.difficile in CF, including a description of the first faecal transplantation in this patient population.

Airway persistence by the emerging multi-azole-resistant Rasamsonia argillacea complex in cystic fibrosis.

Infections caused by Rasamsonia argillacea complex have been reported in various clinical settings. Cystic fibrosis (CF) is one of the main underlying conditions. An observational cohort study of CF patients with Rasamsonia in respiratory samples was conducted. Eight isolates from 6 patients were identified as R. argillacea complex and tested for antifungal susceptibility. All isolates had high MICs to voriconazole and posaconazole and low MECs to echinocandins. Four patients experienced lung function decline in the year preceding first Rasamsonia isolation. This continued in the year following first isolation in 3 out of 4 cases. Antifungal therapy was initiated in 2 patients, to which only one exhibited a clinical response. Three out of 6 patients died within 3 years of isolating Rasamsonia. Genotyping suggests that similar genotypes of Rasamsonia can persist in CF airways. Consistent with other fungi in CF, the clinical impact of airway colonisation by Rasamsonia is variable. In certain patients, Rasamsonia may be able to drive clinical decline. In others, though a clear impact on lung function may be difficult to determine, the appearance of Rasamsonia acts as a marker of disease severity. In others it does not appear to have an obvious clinical impact on disease progression.

Is daily physical activity affected by dynamic hyperinflation in adults with cystic fibrosis?

BACKGROUND: The aim of this study was to investigate the relationship between dynamic hyperinflation and daily physical activity (DPA) in adults with cystic fibrosis (CF). METHODS: Thirty-four clinically stable CF were studied. All patients undertook incremental cardiopulmonary exercise testing (CPET). CPET-related measurements included: oxygen uptake (V'O2), carbon dioxide production (V'CO2), ventilatory profile, work rate (W), inspiratory capacity (IC), end-expiratory lung volume (EELV). PA was assessed using the accelerometer SenseWear Pro3 Armband. RESULTS: Exercise tolerance was reduced in most of patients and the mean V'O2,peak value was 75.2% of predicted (28.5 ± 4.8 ml/min/kg). Seventy % of patients responded to CPET with dynamic hyperinflation. Higher incidence of dynamic hyperinflation was found in CF males compared to CF females (p = 0.026). Patients who developed dynamic hyperinflation during CPET had higher vigorous PA (p = 0.01) and more total energy expenditure (p = 0.006) than patients who did not. EELVΔ was related to activities requiring vigorous intensity and total energy expenditure (R = 0.46, p = 0.001; R = 0.57, p <  0.001). CONCLUSIONS: In adults with CF and mild to moderate lung impairment, DPA might not be limited by dynamic hyperinflation.

Phenotypic variability of R117H-CFTR expression within monozygotic twins.

Whilst cystic fibrosis is a monogenic condition, variation in phenotype exists for the same CFTR genotype, which is influenced by multiple genetic and non-genetic (environmental) factors. The R117H-CFTR mutation has variability directly relating to in cis poly-thymidine alleles, producing a differing spectrum of disease. This paper provides evidence of extreme phenotype variability - including fertility status - in the context of male monogenetic twins, discussing mechanisms and highlighting the diagnostic and treatment challenges.

Cystic Fibrosis Papers of the Year, 2013-2014.

Studies published in the last year in the field of cystic fibrosis have provided more data on the safety and efficacy of a number of therapies, including mutation-specific drugs. There have also been a number of publications on monitoring of early lung disease including the use of lung clearance index and magnetic resonance scanning. Evidence suggests early lung changes may remain relatively static over the first year of life. There are important outcome differences across national patient registries and there is also the increasing recognition of psychological illnesses and possible drug interactions as treatment becomes more complicated and survival improves.

Relationship between pulmonary exacerbations and daily physical activity in adults with cystic fibrosis.

BACKGROUND: The aim of this study was to examine the relationship between pulmonary exacerbations and physical activity (PA) in adults with cystic fibrosis (CF). METHODS: We grouped adults with CF according to their exacerbation status in the year before study enrollment: (1) <1 exacerbation/year; (2) 1-2 exacerbations/year; and (3) >2 exacerbations/year. PA was assessed objectively by means of an accelerometer at the time of study enrollment. RESULTS: Patients with >2 exacerbations/year spent less time in PA; specifically, fewer activities of mild intensity [>3 metabolic equivalents (METs)], and lower active energy expenditure (P = 0.01 and P = 0.03, respectively). After correcting for relevant confounders, PA levels were not related to the exacerbation frequency in the preceding year. PA at moderate intensity (4.8-7.2 METs) or greater (> 7.2 METs) was independently associated with gender and FEV1 % predicted (P = 0.007 and P = 0.04, respectively). Compared with men, women had reduced vigorous activities (P = 0.01) and active energy expenditure (P = 0.01). CONCLUSIONS: Adult CF patients with more pulmonary exacerbations in the preceding year have more advanced disease and are less active than their peers. PA was independently associated with gender and airflow obstruction. Gender differences in PA are evident in CF adults.

Relationship between daily physical activity and aerobic fitness in adults with cystic fibrosis.

BACKGROUND: The best clinical practice to investigate aerobic fitness includes measurements obtained during cardiopulmonary exercise testing (CPET), however it remains an underutilised clinical measure in cystic fibrosis (CF). To investigate this further, different methods of quantifying exercise capacity in CF are required. The possibility that measuring physical activity (PA) by a portable accelerometer could be used to assess the CF aerobic state and could be added among the CPET surrogates has not been investigated. The aim of this study was to examine the relationship between PA and exercise fitness both at submaximal and maximal levels in clinically stable adults with CF. METHODS: Thirty CF patients (FEV1 71 ± 19% predicted) and fifteen healthy controls undertook an incremental CPET on a cycle ergometer. CPET-related measurements included: oxygen uptake (V'O2), carbon dioxide production (V'CO2), ventilatory profile, heart rate (HR) and oxygen pulse (V'O2/HR) throughout exercise and at lactic threshold (LT) and peak. LT measures represent submaximal exercise related data. PA was assessed using the accelerometer SenseWear Pro3 Armband. RESULTS: Moderate (>4.8 metabolic equivalents (METS)) and moderate + vigorous (>7.2 METS) PA was related to V'O2 (p = 0.005 and p = 0.009, respectively) and work rate (p = 0.004 and p = 0.002, respectively) at LT. Moderate PA or greater was positively related to peak V'O2 (p = 0.005 and p = 0.003, respectively). Daily PA levels were similar in CF and healthy controls. Except for peak values, V'O2 profile and the V'O2 at LT were comparable between CF and healthy controls. CONCLUSIONS: In adult CF patients daily PA positively correlated with aerobic capacity. PA measurements are a valuable tool in the assessment of exercise performance in an adult CF population and could be used for interventional exercise trials to optimize exercise performance and health status. PA levels and parameters obtained at submaximal exercise are similar in CF and in healthy controls.

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.

Aspergillus and cystic fibrosis: old disease - new classifications.

PURPOSE OF REVIEW: Aspergillus pulmonary infection has traditionally been recognized as a clinical spectrum of increasing pathogenicity, encompassing saprophytic airways colonization historically regarded of doubtful clinical significance, to allergic bronchopulmonary aspergillosis, chronic cavitatory and life-threatening invasive disease in the immunocompromised host. Whilst the latter two categories are rarely encountered in cystic fibrosis (CF), there is recognition of an extending spectrum of disease yet to be reflected in consensus management guidelines. The purpose of this review is to provide an up-to-date overview of this extending spectrum, with a focus on disease categories and their clinical significance. RECENT FINDINGS: Conflicting evidence regarding the clinical significance of Aspergillus colonization and sensitization in CF, alongside the emergence of a novel disease category 'Aspergillus bronchitis', has led to proposals for the reclassification of Aspergillus disease. In addition, lack of standardization and poor sensitivity of culture-dependent mycology techniques renders clinical and epidemiological interpretation of these isolates challenging. SUMMARY: The role of Aspergillus in the absence of established CF-allergic bronchopulmonary aspergillosis remains unclear. The following review discusses new approaches proposed to categorise the extended spectrum of CF Aspergillus disease, highlighting the need for enhanced microbiological investigation and serological monitoring of patients in light of evidence which differentiates colonization from categories of greater pathogenic potential.

How representative are clinical trial cohorts of the general CF population? Implications for trial planning.

Understanding the number of patients eligible to participate in research is important to design protocols and define research priorities. We reviewed the records of all patients with CF, age 12+, who receive care at our centre. We assessed their eligibility for trial participation based on common trial inclusion/exclusion criteria. 643 patients were included in the analysis, 31 were modulator ineligible(MI). Only 198(31 %) of the total cohort and 7(23 %) of the MI cohort were eligible for participation based on the hypothetical criteria. The most common reason for ineligibility was ppFEV1 ≥90 % followed by clinical instability, complex comorbidity and anticipated inability to adhere to the protocol. We suggest this would be a useful exercise for centres planning to either participate in, or refer subjects into, upcoming trials to undertake for their own cohort. We also make suggestions for protocol designs that optimise the number of patients who are eligible to participate.

Inhaled antimicrobial prescribing for Pseudomonas aeruginosa infections in Europe.

BACKGROUND: Prescribers have an increasing range of inhaled antimicrobial formulations to choose from when prescribing both eradication and chronic suppression regimens in cystic fibrosis (CF). This study aimed to investigate the decision-making process behind prescribing of inhaled antimicrobials for Pseudomonas aeruginosa infections. METHODS: A questionnaire was developed using Microsoft Forms and then forwarded to 57 Principal Investigators (PIs), at each of the CF centres within the European Cystic Fibrosis Society-Clinical Trials Network (ECFS-CTN). Data collection occurred between November 2021 and February 2022. RESULTS: The response rate was 90 % (n = 51/57 PIs), with at least 50 % of CF centers in each of the 17 countries represented in the ECFS-CTN. Physicians used a median of eight factors in their decision-making process with delivery formulations (92.2 %), adherence history (84.3 %), and antibiotic side-effect profile (76.5 %) often selected. Nebulised tobramycin or colistin were frequently selected as the inhaled antimicrobial in first-line eradication (n = 45, 88.2 %) and chronic suppression regimens (n = 42, 82.4 %). Combination regimens were more often chosen in eradication (first-line: n = 35, 68.6 %, second-line: n = 34, 66.7 %) and later chronic suppression regimens (third-line: n = 27, 52.9 %) than monotherapy. For pwCF also prescribed CFTR modulator therapies, most PIs did not alter inhaled antimicrobial regimens (n = 40, 78.4 %), with few pwCF (n = 18, 35.3 %) or PIs (n = 10, 19.6 %) deciding to stop inhaled antimicrobials. CONCLUSIONS: The inhaled antimicrobial prescribing decision-making process is multifactorial. Nebulised tobramycin or colistin are often used in initial eradication and chronic suppression regimens. To date, CFTR modulator therapy has had a limited impact on the prescribing of inhaled antimicrobial regimens.

Levelling the playing field through the London Network of the UK clinical trials accelerator platform.

Cystic fibrosis (CF) is a multisystem, genetic disease with a significantly reduced life expectancy. Despite substantial progress in therapies in the last 10-15 years, there is still no cure. There are dozens of drugs in the development pipeline and multiple clinical trials are being conducted across the globe. The UK Cystic Fibrosis Trust's (CFT) Clinical Trials Accelerator Platform (CTAP) is a national initiative bringing together 25 UK based CF centres to support the CF community in accessing and participating in CF clinical trials. CTAP enables more CF centres to run a broader portfolio of trials and increases the range of CF studies available for UK patients. There are four large specialist CF centres based in London, all within a small geographical region as well as two smaller centres which deliver CF care. At the launch of CTAP, these centres formed a sub-network in a consortium-style collaboration. The purpose of the network was to ensure equity of access to trials for patients across the UK's capital, and to share experience and knowledge. Four years into the programme we have reviewed our practices through working group meetings and an online survey. We sought to identify strengths and areas for improvement. We share our findings here, as we believe they are relevant to others delivering research in regions outside of London and in other chronic diseases.