Long-term daily high and low doses of azithromycin in children with cystic fibrosis: A randomized controlled trial

BackgroundLong-term administration of azithromycin (AZM) in children with cystic fibrosis (CF) has improved outcomes. However, the doses and schedule of administration are not very well studied in children with CF.MethodsA randomized controlled trial was conducted to compare the effect of two doses of azithromycin (5 mg/kg/day and 15 mg/kg/day) on FEV₁ and pulmonary exacerbations in children with cystic fibrosis. Enrolled children were randomly allocated to receive daily azithromycin (5 mg/kg/day or 15 mg/kg/day) for 6 months. Clinical assessment and FEV₁ measurement were performed monthly.Results56 children (28 in high dose group and 28 in low dose group) were enrolled. 47 (24 and 23 children in low and high dose groups) completed 12 months of follow up. There was no difference in clinical scores, FEV₁, pulmonary exacerbation rates between two groups at baseline, 6 months and at 12 months. Per protocol analysis revealed that pulmonary exacerbation increased after discontinuing AZM and there was significantly more increase after 12 months of enrolment in children getting high dose azithromycin. There was no improvement in FEV₁ in either group at the end of treatment period. Children tolerated daily low as well as high dose AZM well for 6 months. There was no significant side effect of azithromycin.ConclusionIn this randomized controlled trial, we did not find differences in the effect of 2 doses (5 mg/kg/day or 15 mg/kg/day) of AZM on change in percentage predicted FEV₁, clinical scores, Pseudomonas colonization rates, pulmonary exacerbations and need for antibiotics. There was increase in exacerbations after stopping azithromycin in both the groups. Our results also suggest that the decrease in the incidence of LRTI persists only till 6 months after discontinuing azithromycin.     

Peak OGTT glucose is associated with lower lung function in young children with cystic fibrosis

BackgroundScreening for Cystic Fibrosis-related diabetes is recommended in patients with CF <10 years old when there are concerns about growth and lung function. The Oral Glucose Tolerance Test (OGTT) is recommended but has not been validated in this cohort. We sought to determine whether the 2-h OGTT, the gold standard diagnostic test for CFRD, detects clinical decline in children with CF <10 years old.MethodsWe analysed blood glucose(BG) levels collected every 30 min during OGTT in 27 children with CF < 10 years old, comparing the 2-hour BG (BG_120min), peak BG (BG_max) and Area Under the Curve(AUC) for glucose and the association with lung function and nutritional status. We also compared the OGTT results with results from Continuous Glucose Monitoring (CGM) performed in 11 participants.ResultsThe BG_max was higher than the BG_120min in 25/27 (93%) participants. There was a significant inverse correlation between BG_max and weight z-score (r_s = −0.56, p = .002) and between BG_max and FEV₁ (r_s = −0.54, p = .014) that was not present for BG_120min. A significant inverse correlation was also identified between fasting insulin level and elevated glucose on CGM, defined as AUC >7.8 mmol/L (r_{s =} − 0.69, p = .027) or as % time > 7.8 (r_s = − 0.76, p = .011).ConclusionsChildren with CF < 10 years of age with higher BG_max on OGTT have lower lung function and weight z- scores that may not be identified using the 2 h OGTT BG_120min. CGM also identifies glucose excursions in young children with CF.     

Dyslipidemia is not associated with the development of glucose intolerance or diabetes in cystic fibrosis

BackgroundA high-fat, high-calorie diet is recommended in patients with cystic fibrosis (CF) as it improves nutritional status, respiratory health and longevity. In the general population, this diet is associated with the risk of diabetes. It is unknown whether dyslipidemic changes might contribute to the development of CF-related diabetes (CFRD).ObjectiveThis study aimed to (i) characterize dyslipidemia and (ii) examine the association between dyslipidemia and development of glucose intolerance.MethodsProspective observational study with serial assessments of pulmonary function, glucose tolerance, and lipid profile. Due to intrinsically low total, HDL and LDL cholesterol in patients with CF, subjects were characterized as having dyslipidemia if they had i) HDL in the lowest quartile and/or ii) hypertriglyceridemia (≥1.7 mmol/L).ResultsA total of 256 patients with CF were included (age: 25.5 ± 7.7 years; BMI: 21.7 ± 3.0 kg/m2; FEV1%: 73.2 ± 22.1%; pancreatic insufficiency: 87%). Amongst these patients, 22.7% had low HDL, 9.0% had hypertriglyceridemia and 3.9% had mixed dyslipidemia. There were no differences in HbA1c (p = 0.583) or estimated insulin resistance [HOMA-IR (p = 0.206) or Stumvoll index (p = 0.397)]. Patients with hypertriglyceridemia had higher fat mass (p = 0.038) and fewer had pancreatic insufficiency. Lipid profiles were similar between subjects with CF and subjects with de novo CFRD. There was no effect of low HDL or hypertriglyceridemia on the development of CFRD over 10 years (p = 0.683).ConclusionIn adult patients with CF, dyslipidemia is not associated with the risk of developing hyperglycemia or CFRD.     

Interleukin-1 is associated with inflammation and structural lung disease in young children with cystic fibrosis

Background

Little is known about the role of interleukin (IL)-1 in the pathogenesis of cystic fibrosis (CF) lung disease. This study investigated the relationship between IL-1 signalling, neutrophilic inflammation and structural lung changes in children with CF.

Impact of azithromycin on serum inflammatory markers in children with cystic fibrosis and new Pseudomonas

Chronic azithromycin improves outcomes in cystic fibrosis (CF), but its mechanism of action is unclear. The OPTIMIZE trial demonstrated improvement in time to first pulmonary exacerbation in children with new Pseudomonas treated with azithromycin. Azithromycin effect on systemic markers of inflammation over 18 months was assessed by change from baseline for high-sensitivity C-reactive protein, myeloperoxidase, calprotectin and absolute neutrophil count in the OPTIMIZE population. Subjects treated with chronic azithromycin or placebo had samples collected at baseline, 39 and 78 weeks of treatment. In 129 subjects, a significant decrease in high-sensitivity C-reactive protein was present at 39 weeks in the azithromycin group compared to placebo, but no significant difference between the groups at 78 weeks. No differences in change from baseline in myeloperoxidase, calprotectin or absolute neutrophil count were present at either time point. This supports the concept of a transient immunomodulatory effect for chronic azithromycin therapy in children with CF.     

Isolation of Enterobacteriaceae in airway samples is associated with worse outcome in preschool children with cystic fibrosis

BackgroundIncreased abundance of Enterobacteriaceae(EB) in the respiratory microbiome of young CF patients was reported to precede Pseudomonas aeruginosa(PA) colonisation. We explored whether impending PA colonisation can be predicted by growth of EB in routine airway cultures and whether EB contribute to CF lung disease severity.MethodsWe retrospectively studied the records of 62 children with CF for growth of EB and PA during the first 5 years of life and subsequent best lung function at ages 5–7 and 9–11 years.ResultsAt least one EB positive month occurred in 36/62 (58%) patients. Median (IQR) age at first EB isolation was 0.4 (0.2–0.8) years. PA isolation before age 5 was more frequent in the EB positive (23/36, 54%) than in EB negative children (10/26, 38%; p = 0.048). EB isolation preceded PA isolation in 19/23 (83%) cases (p = 0.003).Median (IQRf) FEV₁ at age 5 to 7 years was 105% (94–117) in the EB positive group and 108% (102–115) in the EB negative group (p = 0.154). At age 9–11, FEV₁ was lower in EB positive children (99%(88–105) vs 105%(96–110); p = 0.035).Only PA isolation (p = 0.002) before age 5 years was a significant predictor of FEV₁ at age 5–7 years. Both EB isolation (p = 0.033) and PA isolation (p = 0.023) were predictors of the FEV₁ at age 9–11 years.ConclusionIn preschool children with CF, EB were isolated in just over half of the children. In that subgroup PA isolation was more common. Both EB and PA isolation are associated with worse lung function at later age.     

Hypertriglyceridemia is associated with insulin levels in adult cystic fibrosis patients

BackgroundRecent studies have identified hypertriglyceridemic cystic fibrosis patients (CF-TG). However, whether hypertriglyceridemia is associated with an altered metabolic profile remains unknown.ObjectiveTo characterize CF-TG and determine whether triglycerides (TG) levels are associated with metabolic alterations.Methods210 adult CF subjects from the Montreal Cystic Fibrosis Cohort without known diabetes were included in the analysis. All subjects underwent an OGTT to assess glucose tolerance, insulin secretion (insulin AUC) and insulin sensitivity (Stumvoll index). Fasting lipid profiles, pulmonary function (%FEV₁) and BMI were determined. Hypertriglyceridemia (TG > 1.7 mmol/L) was observed in 20 CF patients. These subjects were matched for age, sex and glucose tolerance category with 20 CF patients (CF-normal-TG) and 20 healthy controls that had TG levels below 1.7 mmol/L. Pearson correlations were performed in the complete study sample (n = 210) to examine the associations between TG levels and other parameters.ResultsThe prevalence of hypertriglyceridemia was 9.5%. Compared to CF-normal-TG, CF-TG subjects displayed significantly higher %FEV_1, insulin AUC (AUC_0–120, AUC_0–30, AUC_30–120), cholesterol levels and a higher ratio of total cholesterol to HDL-cholesterol. Pearson analysis demonstrated that TG levels were associated with BMI, %FEV₁, fasting insulin, insulin AUC_0–120 and AUC_30–120, Stumvoll index, cholesterol levels and the ratio of total cholesterol to HDL-cholesterol. All these correlations remained significant after correction for BMI except %FEV₁.ConclusionTG levels are associated with a mild alteration of the metabolic profile. Whether these changes will increase the long-term risk of CF patients in developing cardiometabolic complications remains to be investigated.     

Indoor air pollution exposure is associated with greater morbidity in cystic fibrosis

BackgroundExposure to higher levels of outdoor air pollution is associated with increased morbidity in individuals with cystic fibrosis. Limited information exist regarding the potential adverse effects of indoor air pollution on those with cystic fibrosis.MethodsIndividuals with cystic fibrosis who were enrolled in the Twin and Sibling Study from 2000-2013, self-reported exposure to four known sources of indoor air pollution (secondhand smoke, forced hot air, wood stove and fireplace). Change in lung function, rates of hospitalizations and pulmonary exacerbations were followed over 4 years to compare outcomes in those who were exposed to those who were not exposed.ResultsOf 1432 participants with data on secondhand smoke exposure, 362 (25.3%) were exposed. Of 765 individuals with data on forced hot air exposure, 491 (64.2%) were exposed. Of 1247 participants with data on wood stove exposure and 830 with data on fireplace exposure, 182 (14.6%) and 373 (44.9%) were exposed, respectively. In longitudinal analysis, pediatric individuals either exposed to secondhand smoke or to forced hot air had a 0.60% predicted/year decrease in FEV₁% predicted (P=0.002) or a 0.46% predicted/year decrease in FEV1% predicted (P=0.048), respectively compared to individuals who were not exposed. Adults exposed to secondhand smoke had a 42% increased yearly risk of hospitalization compared to those who were not exposed (P=0.045).ConclusionsOur questionnaire-based data suggest that exposure to sources of indoor air pollution increase morbidity in both the pediatric and adult cystic fibrosis populations. Future studies with quantitative indoor air quality assessments are needed.     

Elevated gamma-glutamyltransferase is associated with mortality in lung transplantation for cystic fibrosis

Cystic fibrosis (CF) is a life-threatening autosomal recessive hereditary disease, affecting multiple organs. In end stage disease, lung transplantation improves the quality of life and prolongs survival. CF liver disease (CFLD) as co-morbidity develops in 8-17% of CF patients. We aimed to investigate the impact of liver injury on prognosis following lung transplantation. Thirty-one patients with CF who underwent double lung transplantation (DLTx) from 1999 to 2009 were included. Post-transplant survival, liver serum parameters as well as INR, creatinine and the MELD-Score were determined preoperatively, 1 day and 4 weeks postoperatively. Prognostic impact of liver function on outcome was analysed. Mean patient age was 25 (15-38) and post-transplant 1 year-survival was 74%, 3 years 71% and 5 years 68%. Patients were grouped according to post-transplant survival, those deceased within the first year as group I (n = 8) and patients who survived longer as group II (n = 23). Group I exhibited significantly elevated gamma-glutamyltransferase (GGT), bilirubin and reduced platelets postoperatively. Low platelet count, increased bilirubin and GGT were associated with mortality after DLTx. Prospective studies are needed to determine a potential use and clinical implications for liver function tests in patients with CF before lung transplantation.     

Neutrophil respiratory burst activity is not exaggerated in cystic fibrosis

BackgroundExaggerated neutrophil-dominated inflammation underlies progressive cystic fibrosis (CF) lung disease. Older studies reported a defective respiratory burst in CF, but more recent studies suggest neutrophil function is normal.MethodsWe measured the amount and rate of reactive oxygen species (ROS) during PMA-stimulated respiratory burst activity in children [70 CF, 13 disease controls, 19 health controls] and adults [31 CF, 14 health controls] in neutrophils harvested from peripheral blood. Blood was collected from participants with CF when clinically stable (60 children, 9 adults) and on hospital admission (38 children, 24 adults) and discharge (18 children, 21 adults) for acute pulmonary exacerbations.ResultsWhen clinically stable, children with CF had lower ROS production [median 318,633, 25% 136,810 - 75% 569,523 RLU] than disease controls [median 599,459, 25% 425,566 - 75% 730,527 RLU] and healthy controls [median 534,073, 25% 334,057 - 75% 738,593 RLU] (p = 0.008). The rate of ROS production was also lower (p = 0.029). In neither children nor adults with CF did ROS production increase on hospital admission for acute pulmonary exacerbation, nor fall prior to discharge. There were no associations between ROS production and high-sensitivity C-reactive protein (indicating systemic inflammation) in either children or adults with CF.ConclusionsOur data do not support a role for exaggerated respiratory burst activity contributing to the exaggerated neutrophil-dominated inflammation seen with CF lung disease.     

Renal impairment in children with cystic fibrosis

BackgroundDue to the improvement in life expectancy in cystic fibrosis (CF), co-morbidities such as renal function impairment may be more frequent.AimTo determine the prevalence of renal disease in children with CF and to identify associated risk factors.MethodsA single-center retrospective study analyzing the genetic, clinical and therapeutic characteristics of 112 children. The estimated glomerular filtration rate (GFR), microalbuminuria and lithiasic risk factors were assessed.ResultsThe median calculated GFR (Schwartz) was 123, 161 and 155 ml/min/1.73 m² in children aged 1, 6 and 15 years, respectively. The cumulative dose of aminoglycosides was not correlated to GFR. Microalbuminuria was present in 22/38 patients. Hyperoxaluria was observed in 58/83 patients and was associated with a severe genotype, pancreas insufficiency and liver disease. Hypercalciuria, hyperuricuria and hypocitraturia were identified in 16/87, 15/83 and 57/76 patients, respectively.ConclusionRenal impairment in CF has various presentations. There appears to be low levels of renal impairment in children with CF. However, the risk of oxalocalcic urolithiasis is enhanced, and GFR may be underestimated by the Schwartz formula. Further studies using measured GFR techniques are thus warranted.     

Airway remodelling in children with cystic fibrosis

Background

The relationship between airway structural changes and inflammation is unclear in early cystic fibrosis (CF) lung disease. A study was undertaken to determine changes in airway remodelling in children with CF compared with appropriate disease and healthy controls.

Methods

Bronchoalveolar lavage and endobronchial biopsy were performed in a cross‐sectional study of 43 children with CF (aged 0.3–16.8 years), 7 children with primary ciliary dyskinesia (PCD), 26 with chronic respiratory symptoms (CRS) investigated for recurrent infection and/or cough and 7 control children with no lower airway symptoms. Inflammatory cells, cytokines, proteases and matrix constituents were measured in bronchoalveolar lavage fluid (BALF). Reticular basement membrane (RBM) thickness was measured on biopsy specimens using light microscopy.

Results

Increased concentrations of elastin, glycosaminoglycans and collagen were found in BALF from children with CF compared with the CRS group and controls, each correlating positively with age, neutrophil count and proteases (elastase activity and matrix metalloproteinase‐9 (MMP‐9) concentration). There were significant negative correlations between certain of these and pulmonary function (forced expiratory volume in 1 s) in the CF group (elastin: r = −0.45, p<0.05; MMP‐9:TIMP‐1 ratio: r = −0.47, p<0.05). Median RBM thickness was greater in the CF group than in the controls (5.9 μm vs 4.0 μm, p<0.01) and correlated positively with levels of transforming growth factor‐β₁ (TGF‐β₁; r = 0.53, p = 0.01), although not with other inflammatory markers or pulmonary function.

Conclusions

This study provides evidence for two forms of airway remodelling in children with CF: (1) matrix breakdown, related to inflammation, proteolysis and impaired pulmonary function, and (2) RBM thickening, related to TGF‐β₁ concentration but independent of other markers of inflammation.Newborn infants with cystic fibrosis (CF) have structurally normal airways but, at the time of death or lung transplantation, there is severe airway destruction and extensive bronchiectasis.¹ It has been assumed that these structural airway wall changes have occurred secondary to infection and inflammation. In asthma, airway remodelling has been thought to follow chronic airway inflammation,² but recent evidence has challenged this assumption, suggesting instead that remodelling may be an independent parallel process.³ Whether remodelling in CF is secondary to infection and inflammation or a separate process is of potential importance; if the former, then treatment of infection and inflammation could preserve airway function. But if remodelling is a separate process, relating to some aspect of cystic fibrosis transmembrane regulator (CFTR) dysfunction, new therapeutic approaches to preserve airway function may be required.Neutrophilic inflammation within the airway lumen in CF is central to the pathophysiology of the disease and can occur within the first few months of life.⁴ However, most previous work on airway wall pathology has come from explanted lungs or at necropsy. Little is known about the nature of histological changes in the airway wall in children with relatively mild disease or early stage disease, and how these changes may relate to inflammation within the airway lumen.Investigation of airway remodelling in CF to date has attempted to establish alterations in airway components, cytokines and proteases that appear important in asthma. Although there may be airway smooth muscle hyperplasia in adult CF biopsies compared with controls,⁵ it is unclear whether there is thickening of the reticular basement membrane (RBM) and whether any of these changes are seen in the paediatric age group.^6,7 However, biopsy immunoreactivity against transforming growth factor‐β₁ (TGF‐β₁), a cytokine known to be pro‐fibrotic in vitro,⁸ appeared to be associated with a better clinical picture.⁷ Increased levels of matrix metalloproteinase‐9 (MMP‐9) have been found in sputum and bronchoalveolar lavage fluid (BALF) from children with CF.^9,10 Furthermore, increased breakdown products of airway matrix components have been found in urine¹¹ and sputum¹² of patients with CF, but with no clear relationship with pulmonary function.We have previously shown that infants with CF have impaired lung function at diagnosis, irrespective of current or previous respiratory problems,¹³ and that there is no catch‐up in lung function in the preschool years, despite intensive treatment in specialist centres.¹⁴ We therefore hypothesised that structural airway wall changes are present early in the course of CF and that, as with atopic asthma, they may not be directly related to infection or inflammation. To this end, we compared endobronchial biopsies and BALF from children with CF with those from disease and healthy control groups. We studied matrix degradation and thickening of the RBM and looked for relationships with markers of airway inflammation and infection.     

Voriconazole therapy in children with cystic fibrosis

BACKGROUND: There is increasing evidence for the efficacy of the antifungal voriconazole, particularly in immunosuppression. We describe our experience of using voriconazole in children with CF. METHODS: We performed a retrospective case note review of children with CF treated with voriconazole in a single centre over an 18 month period. RESULTS: A total of 21 children aged 5 to 16 years (median 11.3) received voriconazole for between 1 and 50 (22) weeks. Voriconazole was used as monotherapy in 2 children with recurrent allergic bronchopulmonary aspergillosis (ABPA); significant and sustained improvements in clinical and serological parameters for up to 13 months were observed, without recourse to oral steroids. Voriconazole was used in combination with an immunomodulatory agent in a further 11 children with ABPA, with significant improvement in pulmonary function and serology. 8 children without ABPA but who had recurrent Aspergillus fumigatus isolates and increased symptoms also received voriconazole; this group did not improve with treatment. Adverse effects occurred in 7 children (33%: photosensitivity reaction 3, nausea 2, rise in hepatic enzymes 1, hair loss 1). CONCLUSIONS: Voriconazole may be a useful adjunctive therapy for ABPA in CF. Voriconazole monotherapy appears to be an alternative treatment strategy when oral corticosteroids may not be suitable.     

Early glucose abnormalities are associated with pulmonary inflammation in young children with cystic fibrosis

BackgroundChildren with CF are insulin deficient from infancy but very little is known about the impact of glucose abnormalities in early life. We aimed to identify and describe interstitial glucose levels in CF children <6 years and to evaluate the association with pulmonary infection and inflammation.MethodsWe assessed 18 children (5 females) with median age of 3.2 years (range 0·9–5.5) with Continuous Glucose Monitoring for 3 days. Bronchoalveolar lavage (BAL) fluid was cultured for known pathogenic microbial agents and assessed for total white blood cells, percentage of neutrophils and IL-8 level.ResultsPeak sensor glucose (SG) was >11.1 mmol/L in 39% of participants. The percentage neutrophil count on BAL was positively correlated with elevated SG (peak SG r_s = 0.48, p = .044) and with glucose variability (SG standard deviation r = 0.62, β = 38.5, p = .006). BAL IL-8 level was significantly correlated with all measures of CGM hyperglycemia including % time > 7.8 mmol/L (p = .008) and standard deviation (p < .001). Participants with a history of Pseudomonas aeruginosa had a higher % time > 7.8 mmol/L glucose (16% versus 3%, p = .015).ConclusionChildren with CF frequently demonstrate elevated SG levels before age 6 years, which are associated with increased pulmonary inflammation and Pseudomonas aeruginosa infection. Transient SG elevations into the diabetic range (≥11.1 mmol/L) were identified in children from 1 year of age.     

Cystic fibrosis newborn screening does not delay the identification of cystic fibrosis in children with negative results

Background

Several studies have demonstrated the benefit of Cystic Fibrosis Newborn Screening (CFNBS) for early diagnosis and, hence, intervention but the impact of CFNBS on those children not detected on CFNBS is not known. CFNBS may provide false reassurance that all CF has been detected and, therefore, lead to a delay in the diagnosis of children with CF which is not detected on CFNBS. The aim of this study was to determine the impact of CFNBS on the presenting features of children with CF where CF was not detected on CFNBS.

Methods

Subjects at the CFNBS center were selected if CF was identified subsequent to a negative CFNBS with subjects at the No CFNBS selected based on the absence of ΔF508 mutations. Children presenting with features that would lead to investigation for CF independent of clinical status were excluded. Presenting features at diagnosis and pulmonary function at 6 years of age were extracted from medical records.

Results

Twelve children from the CFNBS site and 19 from the No CFNBS site were included in the analysis. The only significant difference between the two in features at diagnosis was lower mean weight z-scores at the No CFNBS site (− 2.9 ± 1.8) compared to the CFNBS center (− 1.4 ± 1.3, p < 0.05). Age at diagnosis, presenting complaint and nutritional status did not differ by site. Growth parameters and pulmonary function at 6 years of age showed no differences between sites.

Conclusions

This study demonstrates that access to CFNBS does not result in delay in diagnosis or poorer outcomes in those children for whom CF was not detected on CFNBS. In addition, children with CF not detected on CFNBS present with typical features of CF and sweat chloride results that are diagnostic of CF.     

Temporal trends in healthcare resource use and associated costs of patients with cystic fibrosis

BackgroundBetter insights into the natural course of cystic fibrosis (CF) have led to treatment approaches that have improved pulmonary health and increased the life expectancy of affected individuals. This study evaluated how the combination of modified demographics and changes in CF management impacted resource consumption and the cost of care.MethodsMedical records of CF patients from 2006 to 2016 in the French CF Registry were linked to their corresponding claims data (SNDS). Medications, medical visits, procedures, hospitalisations, and indirect costs were annualized by calendar year from 2006 to 2017.ResultsOf the 7,671 patients included in the French CF Registry, 6,187 patients (80.7%) were linked to the SNDS (51.9% male, mean age = 24.7 years). The average cost per patient was €14,174 in 2006, €21,920 in 2011 and €44,585 in 2017. Costs associated with hospital stays increased from €3,843 per patient in 2006 to €6,741 in 2017. In 2017, the mean cost per CF patient was allocated as follows: 72% for medications (of which 51% for modulator therapies), 15% for hospital stays, 7% for medical visits, 3% for indirect costs, 2% for medical devices, 1% for outpatient medical procedures.ConclusionThere was a strong increase in the mean annual cost per CF patient between 2006 and 2017, mostly due to the cost of therapy after the introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulators. The combination of an increase in the number of CF patients – particularly adult patients – and an increase in the annual cost per patient led to a substantial increase in the total cost of CF disease care for the health systems.