Clinical, economic, and societal burden of cystic fibrosis and the impact of the CFTR modulator, lumacaftor/ivacaftor: an assessment using linked registry data in Sweden.

AIMS: We aimed to describe the clinical, economic, and societal burdens of cystic fibrosis (CF) and impact of CF transmembrane conductance regulator modulator (CFTRm) treatment on people with CF, caregivers, and healthcare systems. MATERIAL AND METHODS: This retrospective study used linked real-world data from Swedish national population-based registries and the Swedish CF Quality Registry to assess clinical, economic, and societal burden and CFTR impact in CF. Records from people with CF and a ten-fold control population without CF matched by sex, birth year, and location were compared during 2019. Outcomes for a subset aged >6 years initiating lumacaftor/ivacaftor (LUM/IVA) in 2018 were compared 12 months pre- and post-treatment initiation. RESULTS: People with CF (n = 743) had >10 times more inpatient and outpatient specialist visits annually vs controls (n = 7406). Those aged >18 had an additional 77·7 (95% CI: 70·3, 85·1) days of work absence, at a societal cost of €11,563 (95% CI: 10,463, 12,662), while caregivers of those aged <18 missed an additional 6.1 (5.0, 7.2) workdays. With LUM/IVA treatment, people with CF (n = 100) had significantly increased lung function (mean change in ppFEV1 [3·8 points; 95% CI: 1·1, 6·6]), on average 0·5 (95% CI: -0·8, -0·2) fewer pulmonary exacerbations and 45·2 (95% CI: 13·3, 77·2) fewer days of antibiotics. Days of work lost by caregivers of people with CF aged <18 decreased by 5·4 days (95% CI: 2·9, 7·9). CONCLUSION: CF is associated with a high clinical economic and societal burden in Sweden. Improvements in clinical status observed in people with CF treated with LUM/IVA were reflected in reduced caregiver and societal burden.

Cystic fibrosis (CF) is a disease caused by a single faulty gene called CFTR, which affects the lungs, pancreas, and other organs. Medications known as CFTR modulators help improve the function of this faulty gene and have shown benefits for people with CF. In Sweden, two such medicines, lumacaftor and ivacaftor (LUM/IVA), have been available since July 2018 for treating CF. This study looks at the impact of CF on patients, caregivers, and the healthcare system, as well as the benefits of CFTR modulators. Using data from Swedish national healthcare and social insurance registries, the study compared 743 people with CF in 2019 to about 7400 people without CF, matched by sex, birth year, and location. The findings show that people with CF had 24 times higher direct healthcare costs, including outpatient visits, hospitalizations, and CF-related medications, totaling 23,233 Euros. Indirect costs, such as work absences for those over 18 with CF anssd caregivers' absences to care for sick children, were 9,629 Euros, which is five times higher than the general population. Those over 6 years old treated with LUM/IVA showed improved lung health, reduced hospitalizations (though not significantly), and needed fewer antibiotics. Caregivers' work absences decreased, but there was no change in work absences for adults with CF. Overall, treatment with LUM/IVA improved clinical outcomes and reduced the burden on caregivers and society.

Effectiveness of manual therapy interventions in cystic fibrosis care: a pilot study.

BACKGROUND: Cystic fibrosis (CF) is a severe genetic condition that affects multiple organ systems and imposes a substantial treatment burden. Regarding the lungs and airways, the progressive pathophysiological changes place a significant strain on the musculoskeletal components of the respiratory system for people with CF. This pilot study investigated the effectiveness of manual therapy interventions (MTIs) on thoracic mobility, respiratory muscle strength, lung function, and musculoskeletal pain. METHOD: A study with a pretest-posttest design was conducted with 15 eligible people with CF at the Sahlgrenska University Hospital CF Centre. After an initial set of diagnostic tests at baseline, the participants underwent eight weekly 30-min MTIs. The MTIs included passive joint mobilisation and soft tissue manipulation of primary and secondary anatomical areas of the musculoskeletal respiratory system. On the day of the final intervention, the baseline measurements were repeated. RESULTS: Trends of increased thoracic mobility were observed following the intervention, with a statistically significant increase in respiratory muscle strength. No change in lung function was observed. Musculoskeletal pain before and after the intervention showed a significant decrease in tender points, and all participants reported positive experiences with MTIs. CONCLUSION: MTIs may improve thoracic mobility, alleviate pain, and enhance respiratory muscle strength in people with CF. Further research is needed to confirm their potential role as a CF physiotherapy supplement. CLINICAL TRIAL ID: NCT04696198.

Musculoskeletal aspects of respiratory function in cystic fibrosis: a cross-sectional comparative study.

Background: Respiration is an intricate interaction between visceral and musculoskeletal structures. In cystic fibrosis (CF), the airways and lungs are subject to progressive obstruction and destruction. However, knowledge about the musculoskeletal aspects of respiratory function and symptoms is still limited in this patient group. Methods: In a cross-sectional comparative study, 21 adults with CF enrolled at the Gothenburg CF Centre were matched with 42 healthy controls. The two groups were examined and compared in terms of thoracic mobility, respiratory muscle strength, lung function, and musculoskeletal pain in accordance with a predefined protocol. Results: Significant differences were observed between the groups in the number of tender points, thoracic excursion, forced vital capacity (FVC), and forced expiratory volume (FEV). The CF group also demonstrated a tendency toward reduced function in other measurements, although these were not statistically significant. Conclusion: This cross-sectional study revealed that people with CF have reduced thoracic mobility and an increased prevalence of muscular tender points, alongside decreased lung function, compared to healthy controls. These findings stress the need for greater emphasis on the often-overlooked musculoskeletal aspects of CF care, especially as people with CF are living longer and may require more musculoskeletal health support.

In vitro stimulation with nontuberculous mycobacteria induced a stronger cytokine response in leukocytes isolated from individuals with latent tuberculosis compared to those isolated from active tuberculosis or cystic fibrosis patients.

Mycobacterium tuberculosis and opportunistic environmental non-tuberculous mycobacteria (NTM) can cause severe infection. Why latent tuberculosis infection advances to active disease, and why some individuals with cystic fibrosis (CF) develop pulmonary infections with NTM is still poorly understood. The aim of this study was to investigate the effector function of peripheral blood mononuclear cells (PBMC) from individuals with active or latent tuberculosis, individuals with CF with or without pulmonary NTM-infection and healthy controls, by measuring cytokine response to in vitro stimulation with different species of NTMs. The cytokine concentrations of IL-17A, IL-22, IL-23, IL-10, IL12p70 and IFN-γ were measured in PBMC-culture supernatants after stimulation with NTMs. PBMCs from individuals with latent tuberculosis infection showed strong IL-17A, IL-22, and IFN-γ responses compared to individuals with active tuberculosis or CF. IL-10 production was low in both tuberculosis groups compared to the CF groups and controls. This study suggests that IL-17A and IL-22 might be important to keep tuberculosis in a latent phase and that individuals with CF with an ongoing NTM infection seem to have a low cytokine response.

Thoracic configuration in patients ageing with cystic fibrosis: A retrospective single-blinded cohort study.

BACKGROUND: In patients with cystic fibrosis (CF), thoracic morphology and its role in respiratory function is conditioned by anthropometric factors, as well as by pathological changes. While the lungs are continuously monitored, examinations of potential thoracic cage adaptations to the disease are rare. Hence, the aim of this study was to investigate thoracic configuration, and its correlation to spirometry measures over time. METHODS: In total, 344 high-resolution computed tomography (HRCT) examinations from 90 patients were assessed and analysed. Those results were subsequently related to spirometry measurements performed within the same period. RESULTS: The cohort displayed no homogenous change in thoracic configuration over time, and correlation between thoracic area and spirometry variables could not be supported statistically. CONCLUSIONS: Although the current study included a larger cohort of patients with CF compared to previous studies on thoracic morphology, no patient group-specific changes in thoracic configuration were revealed. Furthermore, no correlations between structural findings and functional respiratory measurements were found.

EVALUATION OF TWO CHEST TOMOSYNTHESIS CYSTIC FIBROSIS SCORING SYSTEMS USING HIGH-RESOLUTION COMPUTED TOMOGRAPHY BRODY SCORING AS REFERENCE.

PURPOSE: To evaluate two chest tomosynthesis (CTS) scoring systems for cystic fibrosis (CF), one system developed by Vult von Steyern et al. (VvS) and one system based on the Brody scoring system for high-resolution computed tomography (HRCT) (modified Brody (mB)). Brody scoring of HRCT was used as reference. METHODS: In conjunction with routine control HRCT at clinical follow-up, 10 consecutive adult CF patients underwent CTS for research purposes. Four radiologists scored the CTS examinations using the mB and VvS scoring systems. All scores were compared to the Brody HRCT scores. The agreement between the evaluated CTS scoring systems and the reference HRCT scoring system was determined using Spearman's rank correlation coefficient and the intraclass correlation coefficient (ICC). MAJOR FINDINGS: Spearman's rank correlation coefficient showed strong correlations between HRCT score and both the mB and the VvS CTS total scores (median rs = 0.81 and 0.85, respectively). The ICC showed strong correlation between the CTS scoring systems and the reference: 0.88 for mB and 0.85 for VvS scoring. The median time for scoring was 20 and 10 minutes for the mB and VvS scoring systems, respectively. CONCLUSIONS: Both evaluated CTS scoring systems correlate well with the reference standard Brody HRCT scoring. The VvS CTS scoring system has a shorter reading time, suggesting its advantage in clinical practice.

Th17 associated cytokines in sputum samples from patients with cystic fibrosis.

Cystic fibrosis (CF) is a genetic disease leading to chronic bacterial airway infection and inflammation. T helper 17 (Th17) cells are identified by their production of interleukin (IL)-17A, which recruit neutrophils to the site of airway infection. IL-23 is an important inducer of IL-17 and IL-22 production. The aim of this study was to study the role of Th17 cells in CF airway infection by measuring the levels of Th17 associated cytokines in sputum from CF patients with or without airway infection and by comparison with non-CF-controls. In a cross-sectional screening study, cytokine levels were measured with a Th17 multiplex cytokine ELISA. Significantly lower levels of IL-17A and IL-23 were found in sputa from infected CF patients. The lowest levels of IL-17A were found in patients chronically infected with P. aeruginosa, which also had the lowest IL-17/IL-22 ratio, while children had a higher ratio. Children also had higher IL-23 levels than adults. IL-1ß and IL-10 were significantly lower in CF sputum compared to controls. Thus, in our study CF patients with chronic infections had a lower production of Th17 associated cytokines in sputum compared with non-infected CF patients and infected patient without CF.

Patient acceptance and outcome of mental health screening in Swedish adults with cystic fibrosis.

PURPOSE: Anxiety and depression are common among adults with cystic fibrosis (CF), and the International Committee on Mental Health in CF (ICMH) recommends annual screening for mental health problems. We implemented screening according to the recently published guidelines and assessed the results from the first year, as well as the patients' attitude to annual screening METHODS: Adult patients attending Gothenburg CF-center from Feb 2015 to Dec 2016 completed the GAD-7 (anxiety) and PHQ-9 (depression) forms at the time of their annual review. In addition, questions regarding the screening process and instruments used were asked. RESULTS: All invited patients (n = 100, 52% males, 2% lung transplanted), with a median age of 28 years (range 18-65), agreed to participate. In general (83%), the patients were positive to screening on an annual basis. No significant differences in total GAD-7 and PHQ-9 scores were found when comparing men and women. Patients younger than 30 years of age reported more symptoms of anxiety compared to older patients (p = 0.02). There were 21 (21%) patients with scores > 10 for GAD-7 and/or PHQ-9 indicating at least moderate anxiety or depression. Scores > 10 were reported by 15 patients on GAD-7, 15 patients on PHQ-9, and 9 patients reported scores above 10 on both measures. CONCLUSION: The patients considered annual check-ups for mental health issues important. Although the screening results are reassuring, the group is heterogenic and younger individuals should be given extra attention. Follow-up over longer time will provide more robust data.

Survival after lung transplantation for cystic fibrosis in Sweden.

Objectives: In Sweden, lung transplantation has been performed in patients with end-stage lung disease since 1990. We assessed survival after lung transplantation for cystic fibrosis (CF) with focus on early mortality and outcome for patients infected with certain multiresistant bacteria, considered a relative contraindication for lung transplantation. Methods: Review of CF and transplant databases and patient charts. The Kaplan-Meier method and log-rank test were used for survival analysis and group comparison. Results: From November 1991 to December 2014, 115 transplantations were performed in 106 CF patients (9 retransplantations): 3 heart-lung, 106 double lung-, 1 double lobar- and 5 single lung transplantations, constituting 13% (115/909) of all lung-transplant procedures performed in Sweden. The mean age at surgery was 31 (SD 10, range 10-61) years and there were 48% females. Overall 1-year survival after lung transplantation for CF was 86.4%, 5-year survival was 73.7% and 10-year survival was 62.4%. The mean and median survival after transplantation were 13.1 (95% confidence interval (CI): 11-15.3) and 14.6 (95% CI: 9.3-19.8) years, respectively, and there was no significant difference for gender or transplant centre. Extracorporeal membrane oxygenation was used as a bridge to transplantation in 11 cases and five patients received reconditioned lungs. Vascular and infectious complications contributed to eight deaths within the first three postoperative months. The mean survival for 14 patients infected pretransplant with Mycobacterium abscessus or Burkholderia cepacia complex was 8.8 (95% CI: 6.1-11.6) years compared to 13.2 (95% CI: 10.9-15.8) years for patients negative for these bacteria. Nineteen patients (14% of all listed), of whom three were listed for retransplantation, died while waiting a median time of 94 days (range 4 days-2.5 years) after listing. Conclusions: Survival after lung transplantation in Sweden is good, also for patients with pretransplant infection with M. abscessus or B. cepacia complex, and comparable to international data.

VISIBILITY OF STRUCTURES OF RELEVANCE FOR PATIENTS WITH CYSTIC FIBROSIS IN CHEST TOMOSYNTHESIS: INFLUENCE OF ANATOMICAL LOCATION AND OBSERVER EXPERIENCE.

The aims of this study were to assess the visibility of pulmonary structures in patients with cystic fibrosis (CF) in digital tomosynthesis (DTS) using computed tomography (CT) as reference and to investigate the dependency on anatomical location and observer experience. Anatomical structures in predefined regions of CT images from 21 patients were identified. Three observers with different levels of experience rated the visibility of the structures in DTS by performing a head-to-head comparison with visibility in CT. Visibility of the structures in DTS was reported as equal to CT in 34 %, inferior in 52 % and superior in 14 % of the ratings. Central and peripheral lateral structures received higher visibility ratings compared with peripheral structures anteriorly, posteriorly and surrounding the diaphragm (p ≤ 0.001). Reported visibility was significantly higher for the most experienced observer (p ≤ 0.01). The results indicate that minor pathology can be difficult to visualise with DTS depending on location and observer experience. Central and peripheral lateral structures are generally well depicted.

Epidemiology of nontuberculous mycobacteria among patients with cystic fibrosis in Scandinavia.

BACKGROUND: Nontuberculous mycobacteria (NTM) are an emerging threat to cystic fibrosis (CF) patients but their epidemiology is not well described. METHODS: In this retrospective observational study we identified all Scandinavian CF patients with a positive NTM culture from airway secretions from 2000 to the end of 2012 and used national CF databases to describe microbiological and clinical characteristics. RESULTS: During the 13-year period 157 (11%) CF patients were culture positive for NTM at least once. Mycobacterium abscessus complex (MABSC) (45%) and Mycobacterium avium complex (MAC) (32%) were the predominant species with geographical differences in distribution. Younger patients were more prone to MABSC (p<0.01). Despite treatment, less than one-third of MABSC patients with repeated positive cultures cleared their infection and a quarter had a lung transplant or died. CONCLUSION: NTM are significant CF pathogens and are becoming more prevalent in Scandinavia. MABSC and MAC appear to target distinct patient groups. Having multiple positive cultures despite treatment conveys a poor outcome.

Extracorporeal membrane oxygenation as a bridge to lung transplantation: a long-term study.

OBJECTIVES: We investigated early outcomes in patients with end-stage pulmonary disease bridged with extracorporeal membrane oxygenation (ECMO) with the intention to perform lung transplantation (LTx). METHODS: ECMO was used as a bridge to LTx in 20 patients between 2005 and 2013. Most patients suffered from rapid progress of disease and most failed to stabilize on mechanical ventilation. Sixteen patients (10 males, median age 42 years, range 25-59) underwent LTx after ECMO support for a median of 9 (range 1-229) days. Most patients were not on the waiting list while receiving ECMO, but after being assessed were on the waiting list for a median of 6 (range 1-72) days before LTx or death occurred. Median follow-up at 535 (range 36-3074) days was 100% complete, 9 patients have been followed for >1 year and 4 patients have been bridged during 2013. RESULTS: Four patients died on ECMO waiting for a donor and as intention-to-treat, the success for bridging was 80% (16/20) and 1-year survival was 62% (10/16, not including 4 with <1-year follow-up). For those who underwent LTx, 3 patients died in-hospital after LTx on Days 0, 16 and 82, respectively, and currently, 11/16 (69%) are alive and 1-year survival for transplanted patients was 9/12 (75%). Median ICU stay before and after LTx was 9 (range 2-229) days and 20 (range 0-53) days, respectively. At follow-up, lung function was evaluated, and mean forced expiratory volume at 1 s and forced vital capacity were 56±22% of predicted and 74±24% of predicted, respectively. CONCLUSIONS: ECMO used as a bridge to LTx results in acceptable survival in selected patients with end-stage pulmonary disease.

Genotyping of Pseudomonas aeruginosa isolates from lung transplant recipients and aquatic environment-detected in-hospital transmission.

Lung infection with Pseudomonas aeruginosa is common in lung transplant recipients and may lead to severe complications. Bacteriological surveillance aims to detect transmission of microbes between hospital environment and patients. We sought to determine whether genotyping of P. aeruginosa isolates could improve identifications of pathways of infection. From 2004 to 2009, we performed genotyping with multiple-locus variable number of tandem repeats analysis (MLVA) and pulsed-field gel electrophoresis (PFGE) of P. aeruginosa isolates cultured from lung transplant recipients at Sahlgrenska University Hospital, Gothenburg. During a small outbreak in 2008, cultivation and genotyping of isolates from sink and drains samples from the hospital ward were performed. Pseudomona aeruginosa from 11/18 patients were genotyped to unique strains. The remaining seven patients were carriers of a P. aeruginosa strain of cluster A genotype. Pseudomona aeruginosa was isolated in 4/8 water samples, typed by MLVA also as cluster A genotype and confirmed by PFGE to be similar or identical to the isolates from four transplanted patients. In conclusion, genotyping of isolates revealed a clonal relationship between patient and water isolates, indicating in-hospital transmission of P. aeruginosa. We suggest genotyping with MLVA for rapid routine surveillance, with the PFGE method used for extended, confirmatory analyses.

Development of IgG antibodies to Exophiala dermatitidis is associated with inflammatory responses in patients with cystic fibrosis.

BACKGROUND: The clinical importance of airway colonisation by the fungus Exophiala dermatitidis in patients with cystic fibrosis (CF) is unclear. We have previously shown that E. dermatitidis frequently colonises the airways of patients with CF. The aims of the present study were to determine whether patients who are colonised by E. dermatitidis have detectable fungal antigens in the circulation, develop anti-fungal antibodies, and show signs of inflammation and impaired respiratory function. METHODS: We collected sputum and serum samples consecutively from 98 sputum-producing patients with CF aged more than 12 years. The serum samples were subjected to bacterial and fungal culturing and analyses for fungal antigens and inflammatory factors. RESULTS: E. dermatitidis was recovered from 17 (17%) patients, the same isolation rate as for Aspergillus fumigatus. There were no difference regarding the levels of ß-glucan in the sera from E. dermatitidis culture-positive and culture-negative patients with CF. Serological analysis revealed significantly higher levels of IgG antibodies to E. dermatitidis cell wall fragments in the E. dermatitidis culture-positive patients. Patients with higher level of E. dermatitidis IgG antibodies were more often colonised with non-tuberculous Mycobacteria, and less often with Staphylococcus aureus. The increased levels of IgG antibodies directed against E. dermatitidis were positively associated with higher white blood cell counts, increased erythrocyte sedimentation rate, pancreatic insufficiency, intravenous antibiotic treatment, and they were negatively associated with respiratory function (FEV1 % predicted). Overall, 4/17 Exophiala-positive patients were diagnosed as having symptomatic infection with E. dermatitidis and were treated with broad-spectrum azoles. CONCLUSION: E. dermatitidis triggers antibody production and may cause significant airway infection in patients with cystic fibrosis.

Dietary intake and nutritional status in a Scandinavian adult cystic fibrosis-population compared with recommendations.

BACKGROUND: Malnutrition is a well-known complication in cystic fibrosis (CF). There is good evidence that maintaining a normal body-weight correlates well with improved survival in CF. Energy intake in excess of 120% of the estimated average requirement (EAR) has been advised since 1980s. OBJECTIVES: To investigate the nutritional intake and status in the adult Scandinavian CF-population. SUBJECTS/METHODS: A cross-sectional multi-centre study was used to investigate the nutritional status of 456 adult CF-patients (2003 2006). Height and weight were measured and body mass index (BMI) and z-scores were calculated. Pulmonary function was examined by dynamic spirometry. A 7-day pre-coded food record (FR) obtained energy and nutrient intake data in 180 patients. RESULTS: The mean energy intake was 114 (SD 30.0)% of EAR and thus significantly lower than the target of 120% EAR (p< 0.001) for patients with pancreatic insufficiency (PI) (n=136). Mean BMI was 22.0 (SD 2.9), the prevalence of BMI <18 was 13% and the prevalence of BMI ≥25 was 15% (n=136). Mean BMI was 20.8 (SD 2.4) in PI-patients with FEV(1) <70% and 23.2% (SD 3.0), in PI-patients with FEV(1) ≥70%, mean difference 2.4, (95% CI: 1.5, 3.3) (p<0.001), but there was no difference in energy intake. BMI ≥18.5 and a reported energy intake <120% were revealed in 54% of the PI-patients. CONCLUSIONS: The energy intake did not reach the recommended 120% EAR, but the prevalence of underweight was lower than reported in other studies. The recommendation may exceed the requirement for a number of CF-patients. The nutritional status must still be closely monitored and nutritional advice and intervention should be individualised and adjusted to actual needs.

High rate of Exophiala dermatitidis recovery in the airways of patients with cystic fibrosis is associated with pancreatic insufficiency.

The black-pigmented fungus Exophiala dermatitidis is considered to be a harmless colonizer of the airways of cystic fibrosis (CF) patients. The aim of this study was to establish the recovery rate of E. dermatitidis in respiratory specimens from CF patients, transplant recipients, and subjects with other respiratory disorders in Sweden. Second, we wished to determine if particular clinical traits were associated with E. dermatitidis colonization of the airways and the antifungal susceptibility profiles of Exophiala strains. Sputum and bronchoalveolar lavage samples (n = 492) derived from 275 patients were investigated. E. dermatitidis was isolated in respiratory specimens from 19% (18/97) of the CF patients but in none of the other patient categories. All isolates were recovered after 6 to 25 days of incubation on erythritol-chloramphenicol agar (ECA) medium. Morphological and genetic analyses confirmed species identity. Pancreatic insufficiency was positively associated with the presence of E. dermatitidis in sputum samples (P = 0.0198). Antifungal susceptibility tests demonstrated that voriconazole and posaconazole had the lowest MICs against E. dermatitidis. In conclusion, E. dermatitidis is a frequent colonizer of the respiratory tract in CF patients in Sweden and appears to be associated with more advanced disease. Whether E. dermatitidis is pathogenic remains to be elucidated.

Lung transplantation in patients with cystic fibrosis and Mycobacterium abscessus infection.

Mycobacterium abscessus lung disease is difficult to treat and has been considered a strong relative contraindication to lung transplantation. We performed double lung transplantation in three cystic fibrosis patients with ongoing, and a fourth with recent treatment for Mycobacterium abscessus lung infection. Despite prolonged antibiotic courses and adjustment of immunosuppressive therapy the first three patients developed skin infection and abscesses. At follow-up after 1, 3, 5 and 7years respectively no patient had evidence of M abscessus infection and all had stable lung function. Lung transplantation in patients with M abscessus lung infection is feasible but may involve severe complications.