Maintaining normal lung function in children with cystic fibrosis is possible with aggressive treatment regardless of <i>Pseudomonas aeruginosa</i> infections

Cystic fibrosis (CF) is an orphan disease with increased morbidity and mortality, mainly due to chronic pulmonary infections. The symptoms and treatment are complex, and patients are followed at specialised CF centres. The exact treatment and the segregation policies to avoid cross-infection from airway pathogens vary between CF centres, including those in Scandinavian countries. The Scandinavian Cystic Fibrosis Study Consortium published 2002 data on the prevalence, incidence and treatment differences of Pseudomonas aeruginosa infections in eight Scandinavian CF centres.1 This showed some differences in the prevalence of chronic P. aeruginosa infections and treatment, but similar lung function levels. This follow-up study, approximately 10 years later, aimed to identify any changes in the patient population and treatment policies, and five of the eight centres participated in both studies: three in Sweden and two in Denmark. The data were collected from 2010 to 2013, before newborn CF screening was introduced in Denmark in 2016 and CF transmembrane conductance regulator modulators were used in clinical practice. The patients were consecutively included at the time of their annual review. Both studies only included CF patients with pancreatic insufficiency, while patients with lung transplant or patients who received shared care were excluded. We recorded demographic data, lung function and infectious status based on the Leeds criteria2 at inclusion. The use of anti-P. aeruginosa antibiotics in the following year was also recorded. If too few sputum cultures were available during the year, their physician could categorise them as chronically infected if they had been treated as such. Data for the five centres were extracted from the earlier study. The regional ethics committees in each country approved the study, and informed written consent was obtained from all patients, or their parents, as appropriate. Fisher's exact test was used to compare the categorical data, namely the prevalence of chronic infections. The Mann-Whitney U test was used days on antibiotics, a continuous variable with skewed distribution. Logistic regression was used to compare forced expiratory volume in one second (FEV1) between the centres. The statistical analyses were performed using SPSS, version 22.0 (IBM Corp). The comparison of the five centres comprised 738 individuals in 2010–2013 (Table 1), which was 17.3% higher than the 629 in 2002. The segregation policies and antibiotic treatment of P. aeruginosa had not changed. However, the mean age had increased by 2.9 years, from 17.7 to 20.6 years. The prevalence of chronic P. aeruginosa infection had fallen from 44.7% in 2002 to 36.3% in 2010–2013, mainly in the Danish CF centres. The 2002 data showed a lower prevalence of chronic P. aeruginosa infection in the Danish than Swedish paediatric patients under the age of 18 (15.2% versus 30.9%), which was also the case in this study (10.0% versus 22.8%). In both studies, chronically or intermittently infected Danish CF patients received more intravenous or inhaled antibiotics than Swedish patients. Aarhus Denmark n=139 n=113 Copenhagen Denmark n=249 n=238 Gothenburg Sweden n=103 n=93 Stockholm Sweden n=171 n=143 Uppsala Sweden n=76 n=42 Age Mean age at inclusion, years (range) 16.1 (1.1–45.7) (14.6 years) 23.3 (0.3–62.9) (19.5 years) 22.0 (1.1– 55.2) (18.2 years) 20.2 (1.1 – 70.3) (16.9 years) 19.3 (0.1– 48.5) (17.7 years) 77% (18–135) (71%) 74% (21–130) (77%) 79% (25–121) (89%) 81% (20–136) (83%) 77% (23–131) (72%) 66% (18–107) (27.0 years) (49%, 26.9 years) 63% (21–116) (31.6 years) (64%, 28.6 years) 73% (25–121) (29.4 years) (72%, 27.9 years) 72% (20–115) (30.7 years) (68%, 28.7 years) 68% (23–112) (29.6 years) (67%, 28.4 years) 86% (22–135) (9.6 years) (83%, 9.3 years) 94% (45–130) (10.4 years) (94%, 9.8 years) 92% (65–119) (9.8 years) (103%, 10.5 years) 94% (59–136) (9.0 years) (95%, 9.4 years) 89% (51–131) (9.3 years) (79%, 9.0 years) 64% (22–96) (28.9 years) (49%, 26.3 years) 57% (21–102) (36.3 years) (60%, 30.8 years) 71% (39–111) (29.4 years) (67%, 28.5 years) 66% (21–115) (29.4 years) (66%, 29.2 years) 63% (23–112) (31.2 years) (68%, 28.2 years) 86% (22–112) (13.8 years) (83%, 11.2 years) 92% (45–110) (11.3 years) (86%, 15.8 years) 79% (65–93) (14.5 years) (97%, 12.7 years) 92% (66–123) (10.4 years) (88%, 11.6 years) 85% (51.1–110) (10.7 years) (45%, 11.9 years) Lung function levels had not changed between the studies. Swedish patients had higher lung function levels than their Danish peers in the whole adult group (p<0.01) and in the adult subgroup with chronic P. aeruginosa infection (p<0.02). In all centres, patients with chronic P. aeruginosa infection had lower median FEV1 than patients without the infection (p<0.01). The mean FEV1 in the paediatric patients was above 80% of predicted in all centres. The changes since 2002 point to the present trends in CF care, including the significant growth in the number of CF patients with pancreatic insufficiency. The two studies recorded similar lung function, even though the mean age had increased. There were no significant changes in the different segregation and treatment policies, but a number of changes have happened since then. One is that Denmark introduced newborn screening for CF in 2016. The other is the introduction of transmembrane conductance regulators, ivacaftor in 2013 and the combination of ivacaftor and lumacaftor in 2018. These will help the continued increase in CF survival rates, and the reduced mortality rate will lead to an increase in the number of patients followed at each centre. The burden of treatment will not necessarily decrease with increased survival, as more active treatment is needed to keep lung function levels at the present level as the mean patient age increases. Paediatric patients with CF had normal lung function at all centres, regardless of whether they had chronic P. aeruginosa infections or not. This shows that maintaining normal lung function is possible with aggressive treatment. The authors have no conflicts of interest to declare.