Females with cystic fibrosis have a larger decrease in sweat chloride in response to lumacaftor/ivacaftor compared to males.

AIM: To explore which patient-related factors influence sweat test response to CFTR modulators, as well as examining the correlation between the sweat chloride response and ppFEV1 or BMI response, using systematically collected real-life clinical data. METHODS: 160 CF patients were identified who had used lumacaftor/ivacaftor for at least six months. Of these patients, age, sweat chloride levels, ppFEV1 weight and BMI at the start of treatment and after 6 months were collected retrospectively. Pearson and Spearman tests were performed to assess correlations. RESULTS: Females compared to males in this group showed a larger response in sweat chloride (mean difference 10.6 mmol/l, 95% CI: 5.7-15.4) and BMI (mean difference 0.27 kg/m2, 95% CI: 0.01-0.54). A modest but significant correlation was found between patient weight and sweat chloride response (Pearson R = 0.244, p = 0.001), which diminished upon correction for the other factors. The correlation between sex and sweat chloride response remained; R = 0.253, p = 0.001. Sweat chloride response did not correlate with ppFEV1 change or BMI change at 6 months after start of therapy. CONCLUSION: Sweat chloride response is larger in females compared to males, which also explains the negative correlation of weight with the response in sweat chloride concentration after start of lumacaftor/ivacaftor. Sweat chloride response does not correlate with the responses in ppFEV1 and BMI. This information may help the interpretation of sweat test results acquired for the follow up and evaluation of CFTR modulating treatments, and warrants further investigation into the underlying mechanisms of sex differences in response to CFTR modulators.

Clinical effect of lumacaftor/ivacaftor in F508del homozygous CF patients with FEV1 ≥ 90% predicted at baseline.

OBJECTIVE: The first available CFTR modulator combination for homozygous F508del patients, lumacaftor/ivacaftor, has not been tested in patients with percentage predicted (pp)FEV1 > 90 in the phase III trials. The objective of this study is to share real life experience about treatment results in this group. METHODS: In this retrospective observational study, patients aged 6 years or older starting on lumacaftor/ivacaftor in standard care were in strict follow up. For these patients, data were obtained about FEV1, BMI, CFQ-R and sweat chloride before start and after 6 months of treatment, and data about FEV1 and BMI were recorded every 3 months. Exacerbations were recorded continuously. RESULTS: We identified 40 patients with a ppFEV1 ≥ 90 at the start of lumacaftor/ivacaftor who had been in follow up for at least 12 months. After 12 months, ppFEV1 was unchanged, whereas mean absolute change in BMI was +0.88 (p = 0.001) with a mean change in SDS for BMI of +0.26 (p = 0.014). Mean CFQ-R overall score at 6 months improved by 2.6% (p = 0.004) and mean decrease in sweat chloride was -27.3 mEq/L (p = 0.000). Exacerbation rate declined from 1.03 to 0.53/person/year (p = 0.003). One patient discontinued treatment in the first 12 months because of progression of CFRLD, two paused treatment but resumed later. CONCLUSION: Homozygous F508del patients starting lumacaftor/ivacaftor at ppFEV1 ≥ 90 improved significantly in nutritional status, sweat chloride levels and exacerbation rate, but did not respond in ppFEV1. Treatment is well tolerated in this patient group. These effects make it worth considering to treat this group of patients with lumacaftor/ivacaftor.

Early-life antibiotic exposure increases the risk of developing allergic symptoms later in life: A meta-analysis.

This study systematically reviewed and quantified the relationship between exposure to antibiotics during the first 2 years of life and the risk of allergies/atopies including hay fever, eczema, food allergy, positive skin prick testing (SPT), or elevated allergen-specific serum/plasma immunoglobulin (Ig) E levels later in life. PubMed and Web of Science databases were searched for observational studies published from January 1966 through November 11, 2015. Overall pooled estimates of the odds ratios (ORs) were obtained using fixed or random-effects models. Early-life exposure to antibiotics appears to be related to an increased risk of allergic symptoms of hay fever, eczema, and food allergy later in life. The summary OR for the risk of hay fever (22 studies) was 1.23, 95% confidence interval (CI):1.13-1.34; I2 : 77.0%. The summary OR for the risk of eczema (22 studies) was 1.26, 95% CI: 1.15-1.37; I2 : 74.2%, and the summary OR for food allergy (3 studies) was 1.42, 95% CI: 1.08-1.87; I2 : 80.8%. However, no association was found for antibiotics exposure early in life and objective atopy measurements including positive SPT or elevated allergen-specific serum/plasma IgE levels.

Pharmacogenomics of inhaled corticosteroids and leukotriene modifiers: a systematic review.

BACKGROUND: Pharmacogenetics studies of anti-inflammatory medication of asthma have expanded rapidly in recent decades, but the clinical value of their findings remains limited. OBJECTIVE: To perform a systematic review of pharmacogenomics and pharmacogenetics of inhaled corticosteroids (ICS) and leukotriene modifiers (LTMs) in patients with asthma. METHODS: Articles published between 1999 and June 2015 were searched using PubMed and EMBASE. Pharmacogenomics/genetics studies of patients with asthma using ICS or LTMs were included if ≥1 of the following outcomes were studied: lung function, exacerbation rates or asthma symptoms. The studies of Single Nucleotide Polymorphisms (SNPs) that had been replicated at least once were assessed in more detail. RESULTS: In total, 59 publications were included in the systematic review: 26 addressed LTMs (including two genomewide Genome-Wide association studies [GWAS]) and 33 addressed ICS (including four GWAS). None of the GWAS reported similar results. Furthermore, none of the SNPs assessed in candidate gene studies were identified in a GWAS. No consistent reports were found for candidate gene studies of LTMs. In candidate gene studies of ICS, the most consistent results were found for rs28364072 in FCER2. This SNP was associated with all three outcomes of poor response, and the largest effect was reported with the risk of exacerbations (hazard ratio, 3.95; 95% CI, 1.64-9.51). CONCLUSION AND CLINICAL RELEVANCE: There is a lack of replication of genetic variants associated with poor ICS or LTM response. The most consistent results were found for the FCER2 gene [encoding for a low-affinity IgE receptor (CD23)] and poor ICS response. Larger studies with well-phenotyped patients are needed to assess the clinical applicability of ICS and LTM pharmacogenomics/genetics.

Is the raised volume rapid thoracic compression technique ready for use in clinical trials in infants with cystic fibrosis?

UNLABELLED: The European Cystic Fibrosis Society Clinical Trial Network (ECFS-CTN) has established a Standardization Committee to undertake a rigorous evaluation of promising outcome measures with regard to use in multicentre clinical trials in cystic fibrosis (CF). The aim of this article is to present a review of literature on clinimetric properties of the infant raised-volume rapid thoracic compression (RVRTC) technique in the context of CF, to summarise the consensus amongst the group on feasibility and answer key questions regarding the promotion of this technique to surrogate endpoint status. METHODS: A literature search (from 1985 onwards) identified 20 papers that met inclusion criteria of RVRTC use in infants with CF. Data were extracted and tabulated regarding repeatability, validity, correlation with other outcome measures, responsiveness and reference values. A working group discussed the tables and answered 4 key questions. RESULTS: Overall, RVRTC in particular forced expiratory volume in 0.5s, showed good clinimetric properties despite presence of individual variability. Few studies showed a relationship between RVRTC and inflammation and infection, and to date, data remains limited regarding the responsiveness of RVRTC after an intervention. Concerns were raised regarding feasibility in multi-centre studies and availability of reference values. CONCLUSION: The ECFS-CTN Working Group considers that RVRTC cannot be used as a primary outcome in clinical trials in infants with CF before universal standardization of this measurement is achieved and implementation of inter-institutional networking is in place. We advise its use currently in phase I/II trials and as a secondary endpoint in phase III studies. We emphasise the need for (1) more short-term variability and longitudinal 'natural history' studies, and (2) robust reference values for commercially available devices.

Serum retinol levels and pulmonary function in children and adolescents with cystic fibrosis.

BACKGROUND: It has been suggested that higher serum retinol levels could have protective effects on pulmonary function (PF) in patients with cystic fibrosis (CF). However, serum retinol levels will be transiently decreased during pulmonary exacerbation. Therefore, the extent of chronic pulmonary inflammation should be included when describing the association between PF and serum retinol. We assessed the longitudinal relation between serum retinol, immunoglobulin G (IgG) and PF in paediatric CF patients. METHODS: We studied the serum retinol, IgG and forced expiratory volumes in one second (FEV(1)% pred.) of 228 CF patients during a seven-year follow up period. The cross-sectional and longitudinal relations between these variables were assessed. RESULTS: Serum retinol, with medians levels between 1.2 and 1.4 µmol/l, were relatively stable, while median serum IgG gradually increased during the age years. The FEV(1)% pred. was longitudinally inversely associated with serum IgG and age, but not with serum retinol. Each g/l increase in serum IgG level was associated with an accelerated yearly decline in FEV(1)% pred. of 0.5% (95% CI -0.8 to -0.1, p=0.008), and each year increase in age was associated with a 1.7% (95% CI -2.1 to -1.3, p=0.000) decline in FEV(1)% pred. This effect was not observed with respect to serum retinol levels (95% CI -1.9 to 2.2, p=0.570). CONCLUSIONS: In this large sample of children and adolescents with CF, we found no evidence that higher serum retinol levels had protective effects on PF.

A possible alternative exercise test for youths with cystic fibrosis: the steep ramp test.

PURPOSE: The steep ramp test (SRT) can be used to provide an indication of exercise capacity when gas exchange measurements are not possible. This study evaluated the clinical usefulness of the SRT in adolescents with cystic fibrosis (CF) and compared the physiological responses of the SRT with the standard cardiopulmonary exercise test (CPET). METHODS: Forty patients with CF (17 boys and 23 girls; mean ± SD age, 14.7 ± 1.7 years; forced expiratory volume in 1 s, 86% ± 18% of predicted) performed an SRT and a CPET with respiratory gas analysis in a randomized balanced design. Peak work rate (WRpeak), HRpeak, peak minute ventilation (V˙Epeak), and peak oxygen uptake (V˙O2peak) were the main outcome measures. RESULTS: Patients with CF attained values for absolute and relative WRpeak during the SRT of 82% ± 14% and 92% ± 14% of predicted. Nutritional status and degree of airway obstruction did not influence SRT performance. Significantly higher values were attained for WRpeak during the SRT compared with those during the CPET (252 ± 60 vs 174 ± 46 W; P < 0.001), whereas significantly lower values were achieved for HRpeak (168 ± 14 vs 182 ± 12 bpm; P < 0.001), V˙Epeak (59.2 ± 19.5 vs 72.0 ± 20.2 L·min(-1); P = 0.006), and V˙O2peak (36.9 ± 7.5 vs 41.5 ± 7.6 mL·kg(-1)·min(-1); P = 0.008). A strong correlation between WRpeak attained at the SRT and the V˙O2peak achieved during the CPET was found (r = 0.822, P < 0.001). CONCLUSIONS: The SRT seems to be a quick, convenient, and low-cost exercise test that is well-tolerated in patients with CF with mild-to-moderate airway obstruction. It provides an indication of exercise capacity and can potentially be used when exercise testing using gas exchange measurements is not possible.

Prediction of mortality in adolescents with cystic fibrosis.

INTRODUCTION: Lung function, nutritional status, and parameters of exercise capacity are known predictors of mortality in patients with cystic fibrosis (CF). The aim of the current study was to use these important parameters to develop a multivariate model to predict mortality in adolescent patients with CF. METHODS: A total of 127 adolescents with CF (57 girls) with a mean age of 12.7 ± 0.9 yr and a mean percentage of predicted forced expired volume in 1 s (FEV1% predicted) of 77.7% ± 15.6% were included. Cardiopulmonary exercise testing-derived parameters, nutritional status, and resting lung functions were dichotomized according to the criterion value determined using receiver operating characteristic curves. Body mass index (BMI), FEV1%predicted, predicted peak oxygen uptake corrected for body weight (VO2 peak/kg%predicted), peak minute ventilation (VE peak), peak VE/VO2, peak VE/VCO2, and breathing reserve were included in a multivariate model. The Cox proportional hazards model was used to determine the combination of parameters that best predicted mortality and/or lung transplantation. RESULTS: The mean duration of follow-up was 7.5 ± 2.7 yr, during which, nine of the 127 patients (7.1%) died and six (4.7%) underwent lung transplantation. Mortality in this population was best predicted by the model that included FEV1%predicted (hazard ratio, 17.13; 95% confidence interval (CI), 3.76-78.06), peak VE/VO2 (hazard ratio, 5.92; 95% CI, 1.27-27.63), and BMI (hazard ratio, 5.54; 95% CI, 1.82-16.83). CONCLUSIONS: The currently developed model consisting of BMI, FEV1%predicted, and VE/VO2 is a strong predictor of mortality rate in adolescents with CF. This prediction equation may be useful in clinical practice to detect patients with a high risk of mortality and to provide them with additional therapy earlier.

Survey of clinical infant lung function testing practices.

BACKGROUND: Data supporting the clinical use of infant lung function (ILF) tests are limited making the interpretation of clinical ILF measures difficult. OBJECTIVES: To evaluate current ILF testing practices and to survey users regarding the indications, limitations and perceived clinical benefits of ILF testing. METHODS: We created a 26-item survey hosted on the European Respiratory Society (ERS) website between January and May 2010. Notifications were sent to members of the ERS, American Thoracic Society and the Asian Pacific Society of Respirology. Responses were sought from ILF laboratory directors and pediatric respirologists. The survey assessed the clinical indications, patient populations, equipment and reference data used, and perceived limitations of ILF testing. RESULTS: We received 148 responses with 98 respondents having ILF equipment and performing testing in a clinical capacity. Centers in North America were less likely to perform ≥50 studies/year than centers in Europe or other continents (13% vs. 41%). Most respondents used ILF data to either "start a new therapy" (78%) or "help decide about initiation of further diagnostic workup such as bronchoscopy, chest CT or serological testing" (69%). Factors reported as limiting clinical ILF testing were need for sedation, uncertainty regarding clinical impact of study results and time intensive nature of the study. CONCLUSIONS: Clinical practices associated with ILF testing vary significantly; centers that perform more studies are more likely to use the results for clinical purposes and decision making. The future of ILF testing is uncertain in the face of the limitations perceived by the survey respondents.

Lung clearance index: evidence for use in clinical trials in cystic fibrosis.

The ECFS-CTN Standardisation Committee has undertaken this review of lung clearance index as part of the group's work on evaluation of clinical endpoints with regard to their use in multicentre clinical trials in CF. The aims were 1) to review the literature on reliability, validity and responsiveness of LCI in patients with CF, 2) to gain consensus of the group on feasibility of LCI and 3) to gain consensus on answers to key questions regarding the promotion of LCI to surrogate endpoint status. It was concluded that LCI has an attractive feasibility and clinimetric properties profile and is particularly indicated for multicentre trials in young children with CF and patients with early or mild CF lung disease. This is the first article to collate the literature in this manner and support the use of LCI in clinical trials in CF.

Chronic infection and inflammation affect exercise capacity in cystic fibrosis.

Pulmonary function and nutritional status are important determinants of exercise capacity in patients with cystic fibrosis (CF). Studies investigating the effects of determinants, such as genotype or infection and inflammation, are scarce and have never been analysed in a multivariate longitudinal model. A prospective longitudinal cohort study was performed to evaluate whether genotype, chronic inflammation and infection were associated with changes in exercise capacity. Furthermore, we investigated whether exercise capacity can predict clinical outcome. 504 exercise tests of 149 adolescents with CF were evaluated. Maximal oxygen uptake corrected for body mass % predicted declined 20% during adolescence, and was associated with immunoglobulin (Ig)G levels and chronic Pseudomonas aeruginosa infection. A lower exercise capacity was associated with a higher mortality, steeper decline in pulmonary function and greater increase in IgG levels. Since a decline in exercise capacity during adolescence was negatively associated with IgG levels and chronic P. aeruginosa infection, these data emphasise the importance of prevention and treatment of chronic inflammation and infections in patients with CF. Furthermore, a lower exercise capacity was associated with a higher mortality rate, steeper decline in pulmonary function and higher increase in IgG levels with increasing age in adolescents with CF. This stresses the value of regular exercise testing for assessing prognosis in adolescents with CF.

Bordetella species in children with cystic fibrosis: what do we know? The role in acute exacerbations and chronic course.

Despite vaccination, pertussis is still endemic in the Netherlands. A literature search was performed to verify what is known about the role of Bordetella species in children with cystic fibrosis, with regard to the incidence of Bordetella infections, the involvement in pulmonary exacerbations and the influence on chronic course. Little is known about the frequency of Bordetella infections and the involvement of Bordetella species both in relation to the chronic course of cystic fibrosis and to pulmonary exacerbations. Since it is difficult to detect Bordetella species in cultures and few sputum cultures investigated have been obtained during an exacerbation, it is likely that the frequency of Bordetella species in CF patients is underestimated. Identification of Bordetella species in these patients may have serious consequences for the treatment of exacerbations in CF. Future research investigating the role of Bordetella species in cystic fibrosis should use specific techniques to detect Bordetella in cultures.

Assessment of CFTR function in homozygous R117H-7T subjects.

BACKGROUND: R117H is a frequent missense mutation included in most CFTR mutation panels. However knowledge about the residual function of R117H-CFTR channels in cystic fibrosis-affected organs, e.g. airways, intestines and sweat glands is presently lacking. METHODS: We evaluated clinical CF symptoms and assessed CFTR function by sweat tests, nasal potential difference and intestinal current measurements in 2 homozygous R117H individuals (7T variant). RESULTS: The CFTR activity in airways and intestine was within the normal range. However both individuals presented with a borderline sweat test and the male patient was infertile. CONCLUSIONS: The lack of impact of the R117H mutation on chloride secretion in intestine and nose contrasts with the ~80% loss of CFTR activity reported in patch clamp studies. Apparently CFTR activity is not rate-limiting for chloride secretion in both tissues at levels >20% of normal, or compensatory factors may operate that are absent in heterologous host cells in vitro.

Is static hyperinflation a limiting factor during exercise in adolescents with cystic fibrosis?

Increased work of breathing is considered to be a limiting factor in patients with cystic fibrosis (CF) performing aerobic exercise. We hypothesized that adolescents with CF and with static hyperinflation are more prone to a ventilatorily limited exercise capacity than non-static hyperinflated adolescents with CF. Exercise data of 119 adolescents with CF [range 12-18 years], stratified for static hyperinflation, defined as ratio of residual volume to total lung capacity (RV/TLC) > 30%, were obtained during a progressive bicycle ergometer test with gas analysis and analyzed for ventilatory limitation. Static hyperinflation showed a significant, though weak association (Φ 0.38; P < 0.001) with a ventilatorily limited exercise capacity (breathing reserve index at maximal effort >0.70; FEV(1) < 80% predicted and reduced exercise capacity, defined as VO(2peak) < 85% predicted). Analysis of association for increasing degrees of hyperinflation showed an increase to Φ 0.49 (P < 0.001) for RV/TLC > 50%. In adolescents with static hyperinflation, peak work rate (W(peak) ; 3.1 ± 0.7 W/kg (75.1 ± 17.3% of predicted), peak oxygen uptake (VO(2peak) /kg (ml/min/kg); 39.2 ± 9.2 ml/min/kg (91.0 ± 20.3% of predicted), peak heart rate (HR(peak) ; 176 ± 19 beats/min) were significantly (P < 0.05) decreased when compared with non-static hyperinflated adolescents (W(peak) 3.5 ± 0.5 W/kg (81.4 ± 10.0% of predicted)); VO(2peak) /kg (ml/min/kg); 43.1 ± 7.5 ml/min/kg (98.0 ± 15.1% of predicted); and HR(peak) 185 ± 14 beats/min). Additionally, no difference was found in the degree of association of FEV(1) (%) and RV/TLC (%) with VO(2peak) /kg(pred) and W(peak) /kg(Pred) , but we found the RV/TLC (%) to be a slightly stronger predictor of VO(2peak) /kg(pred) and W(peak) /kg(Pred) than FEV(1) (%). These results indicate that the presence of static hyperinflation in adolescents with CF by itself does not strongly influence ventilatory constraints during exercise and that static hyperinflation is only a slightly stronger predictor of W(peak) /kg(Pred) and VO(2peak) /kg(Pred) than airflow obstruction (FEV(1) (%)).

No positive effect of rhdnase on the pulmonary colonization in children with cystic fibrosis.

BACKGROUND: Long-term clinical trials have shown that daily treatment with recombinant human deoxyribonuclease (rhDNAse) in patients with mild to moderate cystic fibrosis (CF) improves lung function and decreases the number of respiratory exacerbations. The aim of this study was to analyze the effect of rhDNAse on the bacterial colonization of the airways in children with CF. METHODS: This was a retrospective cohort study. From the database of the CF Center Utrecht, we selected two groups, an rhDNAse group (daily 2.5 mg rhDNAse) and a control group (no rhDNAse). Primary outcome parameter was the difference in change in bacterial colonization between the treatment and control group during 1.5-year. Secondary outcome parameters were changes in lung function (FEV1) and pulmonary exacerbations. RESULTS: Children treated with rhDNAse showed no significant changes in bacterial colonization during the treatment period, apart from an increase of P. aeruginosa positive cultures, both compared to baseline (53.1% versus 25%, p < 0.05) and control group (no change during study period, 37% versus 37%). The change in FEV1 after one year of treatment was +4.0% in the treatment group versus -0.3% in the control group (p = 0.22). There were no significant changes in number of pulmonary exacerbations. CONCLUSIONS: This study showed no significant beneficial decrease in bacterial airway colonization during 1.5-year of treatment with rhDNAse. The positive effects of rhDNAse on the lung function can therefore not be explained by a change in airway colonization.

Pulmonary consolidation and inflammation: inflammatory pseudotumour in young children.

Here we report two children with a pulmonary inflammatory pseudotumour; a rare entity in children, that often initially presents as a pneumonia, but with the possibility of serious consequences if unrecognised and untreated. One of the children presented is 6 months which is extremely young for this tumour. Difficulties in presentation, management strategies and prognosis are described. Certainly, this is a condition that should be considered even in a very young child with an inflammatory condition presenting as a solid lesion in the lung which does not resolve or even progresses.

Comparing 6 and 10 sec exhalation time in exhaled nitric oxide measurements in children.

Standard exhalation time for Fractional exhaled Nitric Oxide (FeNO) measurements is 10 sec but this is difficult for young children. Recommended exhalation time for children is 6 sec, but this was never substantiated in literature. We aimed to investigate the agreement between FeNO values measured with exhalation times of 6 and 10 sec and the preference of children for either method. The study population comprised children aged 5-17 years visiting the Pediatric Pulmonology outpatient clinic. FeNO values, measured during 6 (FeNO-6) and 10 (FeNO-10) sec (random order) using the single-breath online (SBOL) technique, were compared. Preferences for exhalation times were related to FVC values. Ninety-eight children (mean age 10.6 years) were included. Median FeNO-6 (15.2 ppb) and FeNO-10 (13.6 ppb) did not differ significantly (P = 0.259). Mean difference between FeNO-6 and FeNO-10 was -0.3 ppb, limits of agreement ranging from -5.8 ppb to +5.3 ppb. Sixty percent of children with a Forced Vital Capacity (FVC) less than 3 L preferred the FeNO-6 method. We found good agreement between FeNO-6 and FeNO-10, so they can be used interchangeably. An exhalation time of 6 sec was preferred by the majority of subjects with a FVC below 3 L.

Gene expression in CD4+ T-cells reflects heterogeneity in infant wheezing phenotypes.

Although a marked increase in the reporting of wheezing symptoms since the mid-1970s has been described, the underlying immunopathology of the different wheezing phenotypes has not been clarified. Since differences in gene expression might be involved, the objective of the present study was to identify gene expression profiles in CD4+ T-cells from two distinct infant wheezing phenotypes. The gene expression profiles of peripheral CD4+ T-cells were compared by means of microarray analysis of six transient wheezers, six persistent wheezers and seven healthy controls. The differentially expressed genes were subsequently validated by RT-PCR. The differential gene expression profiles reflected common immunological pathways involved in apoptosis or proliferation of T-cells. Furthermore, both wheezing phenotypes showed decreased expression of the complement component 5 receptor 1 gene, a gene involved in the regulation of bronchial responsiveness. Moreover, differences in gene expression profiles were found in genes involved in the immune response against respiratory syncytial virus, such as those encoding signal transducer and activator of transcription 1 and an inflammatory mediator showing enhanced production in asthma (prostaglandin E(2) receptor 2). The present findings suggest that clinical symptoms of wheeze are reflected in common immunological pathways, whereas differences between wheezing phenotypes are, in part, reflected in distinct gene expression profiles.

Radiological and functional changes over 3 years in young children with cystic fibrosis.

The aim of the present study was to evaluate airway disease progression assessed by chest radiology, expiratory interrupter resistance (Rint,exp) and spirometry in young children with cystic fibrosis (CF) over a 3-yr period. Two chest radiographs combined with two R(int,exp) measurements were performed with a 3-yr interval in 21 preschool children (age (mean+/-sd) 3.2+/-0.9 yrs) and 30 schoolchildren with CF (age 7.2+/-1.9 yrs). Chest radiographs were scored using five different CF scoring systems and Rint,exp measurements were expressed as height-adjusted Z-scores. Spirometry was assessed in schoolchildren and the results were expressed as a percentage of predicted values. Chest radiograph scores worsened significantly over the 3-yr period and a tendency towards more pronounced changes was observed, especially for the Wisconsin score, in preschool children. Most preschool and schoolchildren had Rint,exp Z-scores within the normal range at start and follow-up, and the annual change in Rint,exp Z-score was not significant. In schoolchildren, only the forced expiratory volume in one second as a percentage of forced vital capacity declined significantly during the study period. In summary, in young children with cystic fibrosis, chest radiograph scores worsen significantly over time even while lung function remains stable.