Cystic Fibrosis Infants Research Articles

263 RSV Hospitalization in Cystic Fibrosis in the Canadian Registry of Synagis® (Caress) following Prophylaxis (2005–2011)

Background and AimsThe Canadian Registry of Synagis® (CARESS) tracks palivizumab utilization and respiratory syncytial virus (RSV) hospitalizations in high-risk infants including 186 with cystic fibrosis (CF). This study compares respiratory...

Serial Analysis of the Gut and Respiratory Microbiome in Cystic Fibrosis in Infancy: Interaction between Intestinal and Respiratory Tracts and Impact of Nutritional Exposures

ABSTRACTPulmonary damage caused by chronic colonization of the cystic fibrosis (CF) lung by microbial communities is the proximal cause of respiratory failure. While there has been an effort to document the microbiome of the CF lung in pediatric and adult patients, little is known regarding the developing microflora in infants. We examined the respiratory and intestinal microbiota development in infants with CF from birth to 21 months. Distinct genera dominated in the gut compared to those in the respiratory tract, yet some bacteria overlapped, demonstrating a core microbiota dominated by Veillonella and Streptococcus. Bacterial diversity increased significantly over time, with evidence of more rapidly acquired diversity in the respiratory tract. There was a high degree of concordance between the bacteria that were increasing or decreasing over time in both compartments; in particular, a significant proportion (14/16 genera) increasing in the gut were also increasing in the respiratory tract. For 7 genera, gut colonization presages their appearance in the respiratory tract. Clustering analysis of respiratory samples indicated profiles of bacteria associated with breast-feeding, and for gut samples, introduction of solid foods even after adjustment for the time at which the sample was collected. Furthermore, changes in diet also result in altered respiratory microflora, suggesting a link between nutrition and development of microbial communities in the respiratory tract. Our findings suggest that nutritional factors and gut colonization patterns are determinants of the microbial development of respiratory tract microbiota in infants with CF and present opportunities for early intervention in CF with altered dietary or probiotic strategies.

Cystic Fibrosis: The Role of the Small Airways

Cystic fibrosis (CF) infants are born with normal airway anatomy, and dilatation of mucus glands in smaller airways has been described as the earliest histological changes in the lung of patients. This and other evidence has led to the concept that the small airways may be the region demonstrating initial pathology. Studies clarifying this have been challenged by the lack of a clear definition of what constitutes "small airways" and the difficulties to find accurate measures to quantify and track abnormalities in this region of the lung. Dynamic lung function test are not ideally suited to capture small airway abnormalities as the overall surface area of the small airways is about 40 times greater than that of central airways. Measures that are linked to airway size therefore often fail to capture abnormalities in a disease such as cystic fibrosis that is unevenly distributed throughout the lung. This review summarizes our current understanding of the role of small airways in disease development in cystic fibrosis patients and describes the spectrum of diagnostic tools available to diagnose and follow small airway disease and highlight the opportunities as well as challenges of targeting small airways via aerosol therapy in CF patients.

Hyponatremia in Infants with cystic fibrosis

Hyponatremia can be a presenting symptom of cystic fibrosis in infancy, especially in countries with hot climates. In this issue of The Journal, Guimarães et al from the Universidade Federal de Minas Gerais, Brazil, have evaluated hyponatremia at diagnosis and then longitudinally in 20 infants with cystic fibrosis. They demonstrated that 95% of the patients had hyponatremia at the time of diagnosis, and the serum sodium levels had normalized within the first year. Factors associated with variations in serum sodium were diet and ambient temperature. Their findings indicate that infants with cystic fibrosis in hot countries are still at risk for developing hyponatremia even when receiving an increased salt intake. Article page 285▶ Prevalence of Hyponatremia at Diagnosis and Factors Associated with the Longitudinal Variation in Serum Sodium Levels in Infants with Cystic FibrosisThe Journal of PediatricsVol. 161Issue 2PreviewTo determine the prevalence of hyponatremia at diagnosis in patients with cystic fibrosis and identify the factors associated with changes in serum sodium concentration over time. Full-Text PDF

The influence of sex, gestational age, birth weight, blood transfusion, and timing of the heel prick on the pancreatitis‐associated protein concentration in newborn screening for cystic fibrosis

Pancreatitis-associated protein (PAP) is currently discussed as a marker in newborn screening (NBS) for cystic fibrosis (CF). However, it is not known if PAP concentrations are influenced by sex, gestational age, birth weight, blood transfusion or time of collection and what this would mean for NBS for CF. In 2008 all newborns in part of the Netherlands were screened for CF by an IRT/PAP protocol. PAP concentration was determined by the MucoPAP ELISA (DynaBio), which was modified to a Dissociation Enhanced Lanthanide Fluoroimmunoassay (DELFIA) method following a protocol of PerkinElmer. In healthy newborns, the median PAP concentration was 0.5 μg/l (Interquartile range (IQR 0.3-0.8) whereas this was 3.2 μg/l (IQR 2.0-12.5) in CF infants. PAP concentrations were lower in premature infants 0.94 and 0.91 times for 25 to 31 + 6 weeks GA and 32 to 36 + 6 weeks respectively. A higher PAP concentration was observed in low-birth-weight infants (<2500 gram)(p = 0.001), per 100 gram birth weight gained the PAP concentration decreased with 0.1 %. PAP levels were higher after a blood transfusion, the 95th percentile increased from 1.3 to 3.6 μg/l leading to a higher false-positive rate. The PAP concentration increased when newborn screening was performed more than 168 hours (day 7) after birth (β = 1.63), the 95th percentile increased from 1.3-1.6 μg/l to 4.0 μg/l after 168 hours (72,874 newborns were screened). Sex, birth weight, and gestational age lead to small differences in PAP concentrations without consequences for the screening algorithm. However, blood transfusion as well as performance of the heel prick after 168 hours (7 days) lead to clinically significant higher PAP levels and to a higher risk on a false-positive screening test result.

A qualitative secondary evaluation of statewide follow-up interviews for abnormal newborn screening results for cystic fibrosis and sickle cell hemoglobinopathy

PurposeThe purpose of this qualitative analysis was to assess parental acceptability of large-scale, telephone follow-up regarding their infants’ newborn screening (NBS) results, indicating carrier status for sickle cell hemoglobinopathy (SCH) and cystic fibrosis (CF). MethodsAnalysis of 195 interview transcripts focused on parents’ responses to two open-ended questions: “What was your reaction to being called by me?” and “What do you think of the state NBS program having follow-up people calling parents like you?” Responses were coded using conventional content analysis procedures, and nonparametric tests were performed to analyze quantitative data. ResultsMost parents reported favorable opinions about the follow-up. Favorable opinions were associated with several emotional reactions to receiving follow-up (P <0.001) and three reasons why parents found the interview beneficial (P < 0.05): it provided information, clarified NBS results, and answered questions. Seventeen parents of SCH carriers reportedly had not been told their infant’s NBS results and received them for the first time during the follow-up interview. ConclusionParents of CF and SCH carrier infants had favorable opinions and identified specific benefits to receiving follow-up contact. This analysis demonstrates an information deficit among carrier parents and illustrates the importance of NBS follow-up and need for comprehensive communication and counseling.Genet Med 2012:14(2):207–214

Invasive pneumonia and septic shock in infants as a presentation of cystic fibrosis with vitamin‐deficiency

Herein we describe three infants with the rare presentation of pneumonia with septic shock as their initial medical encounter leading to the diagnosis of cystic fibrosis (CF). At the time of their presentation all three children had significant nutritional deficiency. We initiated an aggressive treatment regimen including nutritional supplementation which resulted in improvement in their pulmonary status and no further recurrences. This series highlights the possible presentation of CF in infancy as a life-threatening invasive infection of Staphylococcus aureus or Pseudomonas aeruginosa. It also supports neonatal screening and emphasizes the role of early attention to nutritional status and vitamin supplementation.

Pseudomonas aeruginosa AES-1 Exhibits Increased Virulence Gene Expression during Chronic Infection of Cystic Fibrosis Lung

Pseudomonas aeruginosa, the leading cause of morbidity and mortality in people with cystic fibrosis (CF), adapts for survival in the CF lung through both mutation and gene expression changes. Frequent clonal strains such as the Australian Epidemic Strain-1 (AES-1), have increased ability to establish infection in the CF lung and to superimpose and replace infrequent clonal strains. Little is known about the factors underpinning these properties. Analysis has been hampered by lack of expression array templates containing CF-strain specific genes. We sequenced the genome of an acute infection AES-1 isolate from a CF infant (AES-1R) and constructed a non-redundant micro-array (PANarray) comprising AES-1R and seven other sequenced P. aeruginosa genomes. The unclosed AES-1R genome comprised 6.254Mbp and contained 6957 putative genes, including 338 not found in the other seven genomes. The PANarray contained 12,543 gene probe spots; comprising 12,147 P. aeruginosa gene probes, 326 quality-control probes and 70 probes for non-P. aeruginosa genes, including phage and plant genes. We grew AES-1R and its isogenic pair AES-1M, taken from the same patient 10.5 years later and not eradicated in the intervening period, in our validated artificial sputum medium (ASMDM) and used the PANarray to compare gene expression of both in duplicate. 675 genes were differentially expressed between the isogenic pairs, including upregulation of alginate, biofilm, persistence genes and virulence-related genes such as dihydroorotase, uridylate kinase and cardiolipin synthase, in AES-1M. Non-PAO1 genes upregulated in AES-1M included pathogenesis-related (PAGI-5) genes present in strains PACS2 and PA7, and numerous phage genes. Elucidation of these genes' roles could lead to targeted treatment strategies for chronically infected CF patients.

Motor delay in cystic fibrosis infants: An observational study

ObjectiveTo verify the prevalence of delay in gross motor development in cystic fibrosis (CF) patients. Study designThis is a cross-sectional observational study. A total of 15 children with CF were included in the analyses. The selection criteria was age between 6 and 42months. Data on demographic, anthropometric, clinical characteristics and severity score (Shwachman) were obtained from patient records. The Bayley Scales of Infant and Toddler Development® - III Edition (BSITD-III) was used to assess motor abilities. ResultsMotor development delay was observed in 26.7% (n=4) of the children and, in 75% of these, there were statistically significant differences between gross and fine motor scores. Low stature, low weight and periods longer than 60days at hospital showed statistically significant association with motor delay (p=0.025, 0.032, 0.003, respectively). ConclusionThe prevalence of motor delay in the studied sample was high, suggesting that biological and ambient conditions of risk present in CF contribute to early motor deficits. Thus, the observation of the motor development in these patients is important for planning an adequate intervention.

196 FEV 1 decline in cystic fibrosis (CF): much attention should be devoted to children and adolescents

Studies suggest that the decline in pulmonary function begins early in CF infants even in those patients without respiratory symptoms. Objective: to describe pulmonary function in CF children younger than 3 years old and to determine if there is any association between pulmonary function and clinical features. Methods: observational and retrospective, study. We collected data from CF patients who underwent an Infant Pulmonary Function Test (IPFT) before the age of three years. IPFTs were assessed by partial flow/volume curves with the rapid thoracicabdominal compression technique to obtain the maximal flow at the functional residual capacity (V′maxFRC). Clinical issues recorded were: age, gender, genetics, pancreatic sufficiency, nutritional status and microbiological findings. Results: 46 patients (31 males) with a median (interquartile range) age of 8 months (5 to 15) were included. Overall V′maxFRC Z score was −0.8 (−1.4 to 0.3), −0.1 (−1.1 to 0.7) in males and −0.9 (−1.8 to 0.3) in females (p =NS). V′maxFRC Z score was −0.3 (−1.1 to 0.2) in children younger than 6 months and −0.1 (−1.3 to 1) in older ones (p =NS). In patients homozygous p.508del V′maxFRC Z score was −0.5 (−1.2 to 0.8) while in patients with other mutations it was −0.2 (−1.2 to 0.6) (p =NS). There was also no statistical difference in V′maxFRC between well-nourished and bad-nourished patients, and between patients with and without Pseudomonas aeruginosa (PA) in sputum. Conclusion: IPFT assessed by partial flow/volume curves was normal in our CF population less than 3 years old. We have not found any difference in pulmonary function comparing CF children with different clinical features.

67* Preclinical evaluation of preventive hypertonic saline therapy for cystic fibrosis-like lung disease in mice

Dehydration of airway surfaces and reduced mucus clearance due to ENaC-mediated increased airway Na+ absorption plays an important role in the pathogenesis of cystic fibrosis (CF) lung disease in patients and causes CF-like lung disease in bENaC-transgenic (bENaC-Tg) mice. Previous clinic trials demonstrated that inhalation of hypertonic saline (HS, NaCl 7%) improved mucus clearance and lung function in CF patients (Donaldson SH et al., 2006), and pilot studies demonstrated that inhalation of HS is well tolerated in young children with CF (Dellon EP et al., 2008). However, effects of HS therapy on airway mucus obstruction and airway inflammation, and the benefits of preventive HS treatment have not been studied. To determine the effects of preventive and late HS therapy on these characteristic features of CF-like lung disease in vivo, we used newborn or 4-week old bENaCTg mice and wild-type littermates and applied intrapulmonary instillation of HS or vehicle alone for 2 weeks. Subsequently, mice were euthanized, bronchoalveolar lavage performed, and lungs processed for histology. We demonstrate that both preventive and late HS treatment provide an effective mucolytic therapy for CF-like lung disease. However, HS promoted airway inflammation in neonates and had no therapeutic effect on airway inflammation in adult bENaC-Tg mice with established CF-like lung disease. These results suggest that potential proinflammatory side effects of early HS treatment should be evaluated before using HS as treatment for CF infants, and that combined mucolytic and anti-inflammatory therapies may be necessary for the treatment of CF lung disease. Supported by EC (MEXT-2004–013666).

Infantile nasal obstruction – An uncommon cause

Abstract We aim to demonstrate the importance of a thorough evaluation in dealing with infants presenting with symptoms of nasal obstruction. We report a case of a male infant who was referred to the ENT service with a history of noisy breathing since birth. Computerized tomography (CT) of his para-nasal sinuses showed opacified maxillary sinuses and bowing of the medial maxillary sinus wall. A sweat test was performed which confirmed the diagnosis of Cystic Fibrosis and genetic analysis demonstrated a Delta F508 homozygous genotype. We advocate a high index of suspicion for Cystic Fibrosis in infants with symptoms of nasal obstruction and evident nasal or para-nasal sinus pathology.

18q deletion in a cystic fibrosis infant, increased morbidity and challenge for correct treatment choices: a case report

Cystic Fibrosis (CF) is the most frequent recessive disease of Caucasian patients. Association with other diseases or syndromes has previously been reported. Co-morbidity may be a challenge for clinicians, who have to face more severe problems.We have described a CF infant, F508del homozygote, diagnosed by neonatal screening, who also had a chromosome 18q terminal deletion [del (18)(q22-qter)]. Some clinical features of the 18q deletion: e.g., cardiopathy, gastro-oesophageal reflux and severe muscular hypotonia, worsened the CF clinical picture and his quality of life, with repeated pulmonary exacerbations and failure to thrive in the first six months of life. The treatment strategy was chosen following an accurate multi-disciplinary team study of overlapping chromosome syndrome and CF symptoms. The use of a gastrostomy device for enteral nutrition together with a new device (Ez-PAP) for chest physiotherapy led to normal growth, a notably reduced hospitalization rate and improved quality of life.This case shows how co-morbidities worsening the clinical course of a "complicated patient" can be faced thanks to unconventional therapies that represent a challenge for clinicians.

Growth and pulmonary outcomes during the first 2 y of life of breastfed and formula-fed infants diagnosed with cystic fibrosis through the Wisconsin Routine Newborn Screening Program

The optimal feeding (breast milk, formula, or a combination) for infants with cystic fibrosis (CF) is unknown. Recommendations from the CF Foundation are based on limited data. We compared growth and pulmonary outcomes between breastfed and formula-fed infants through the age of 2 y. A total of 103 CF infants born in 1994-2006 and diagnosed through newborn screening in Wisconsin were studied. Breastfed infants were classified by the duration of exclusive breastfeeding (ExBF). Exclusive formula-feeding (ExFM) was classified by the formula's caloric density (ie, standard [0.67 kcal/mL (20 kcal/oz) (ExFM20)] throughout infancy or high density [≥0.74 kcal/mL (22 kcal/oz) (ExFM22+)] for some duration of infancy). Fifty-three infants (51% of infants) were breastfed and 50 infants (49% of infants) were ExFM. In breastfed infants, the duration of ExBF was <1 mo (53% of infants), 1-1.9 mo (21% of infants), 2-3 mo (17% of infants), and 4-9 mo (9% of infants). In ExFM infants, 23 infants (46%) received a formula with a high caloric density; approximately half (n = 13) of the ExFM infants received the formula by 6 mo of age. Proportionately more infants with pancreatic sufficiency (n = 9) were ExBF ≥1 mo (44% of infants), and none of the infants were ExFM22+, compared with infants with meconium ileus (n = 24; 13% of infants were ExBF ≥1 mo, and 38% of infants were ExFM22+) or pancreatic insufficiency (n = 70; 25% of infants were ExBF ≥1 mo, and 20% of infants were ExFM22+) (P = 0.02). In infants with pancreatic insufficiency, weight z scores declined from birth to 6 mo (P < 0.0001) in infants who were ExBF ≥2 mo, and the number of Pseudomonas aeruginosa infections through the age of 2 y was fewer in breastfed than in ExFM infants (P = 0.003) but did not differ by the duration of ExBF. For infants with CF, ExBF <2 mo does not compromise growth and is associated with a respiratory benefit.

Bronchoscopy in Cystic Fibrosis Infants Diagnosed by Newborn Screening

There is evidence of early functional and structural changes in babies with cystic fibrosis (CF) diagnosed on newborn screening (NBS). The aim of the present study was to determine the yield of bronchoalveolar lavage (BAL) microbiology and cytology, and 24 hr pH monitoring in a group of CF infants diagnosed on NBS. Infants referred to a tertiary pediatric respiratory center between July 2007 and November 2009 underwent surveillance fiber-optic bronchoscopy (FOB), BAL, and insertion of a 24 hr dual pH probe under a single general anesthetic. We studied 33 infants, median age of 100 days (47-215 days) at the time of FOB. In 9 of 33 (27%) bacterial organisms were identified. Seven of the nine patients (78%) were asymptomatic and only one had had a positive cough swab prior to FOB. Neutrophilia was identified in 18/27 (67%) cases with a median of 11% (6-73%). 13/31 (42%) had an abnormal pH study with a pH index >12%. The high yield of microbiology, cytology, and pH probe investigations in NBS infants justifies invasive surveillance. Longitudinal studies to determine if early aggressive treatment results in improved outcome are awaited.

Linoleic acid supplement in cystic fibrosis: friend or foe?

Linoleic acid supplement in cystic fibrosis: friend or foe?

Predictors of vitamin K status in children and young adults with cystic fibrosis

Cystic fibrosis (CF) is an inflammatory and destructive disease with differentiated clinical expression. Conducted studies revealed the presence of vitamin K deficiencies. However, available results in infants and young children are limited. Therefore, the aim of the present study has been to assess vitamin K status in young CF patients. Material and Methods: Twelve CF infants aged up to 12 months were introduced into the study. Uncarboxylated prothrombin concentrations (Prothrombin Induced by Vitamin K Absence − PIVKA II) as vitamin K deficiency index were measured (ELISA) in all subjects. In addition, nutritional status (standardized body weight), exocrine pancreatic function (fecal elastase-1 concentrations), expression of bronchopulmonary disease and vitamin K dosage were also assessed. Results: All subjects were pancreatic insufficient, pulmonary manifestation was differentiated. In a significant percentage of CF patients body weight deficit was present at diagnosis. Eight children received vitamin K preparations in a dose 0.025−0.4mg/day. In five children receiving supplementation and two nonsupplemented subjects PIVKA II was detectable (range 3.1 to 97 ng/mL). No significant correlation between PIVKA II levels and values of classic (r = −0.468) and conductometric (r = −0.454) sweat test, standardized body weight (r = 0.186), fecal elastase-1 concentrations (r = 0.116), vitamin K supplementation dose (r = 0.334) and the expression of bronchopulmonary disease (r = −0.230) was stated. Conclusions: Vitamin K deficiency seems to be present in cystic fibrosis patients from infancy. No correlation between PIVKA II and parameters assessing the intensity of the disease has been stated.

Protein–energy malnutrition as the first manifestation of cystic fibrosis in infancy

The protein-energy malnutrition (PEM) that is characterized by hypoproteinemia, edema, and anemia has been reported in 5-13% of infants with cystic fibrosis (CF). Due to the surprising higher incidence of PEM as the first presenting manifestation of CF in Macedonia, the aim of the present study was to evaluate the possible risk factors in its development. Clinical and laboratory profiles (hemoglobin, red blood cell count, total serum protein, serum albumin and liver enzyme levels) and genotype data were analyzed in 115 newly diagnosed infants with CF, during the period 1990-2006. PEM manifested in 39 CF infants (33%), usually within the first 5 months of life and in breast-fed infants. Mean hemoglobin, red blood cell count, total serum protein and serum albumin values in the PEM subgroup were, respectively, 76.0 g/L, 2.4 x 10(12)/L, 38.0 g/L and 16.6 g/L. Clinically significant liver involvement was found in 22 patients (56.4%) with PEM. Concerning the molecular basis of CF in these patients, PEM was always associated with triangle upF508, G542X, N1303K and other severe mutations. PEM is a common manifestation of CF in infancy. Early infant age, breast-feeding, impaired liver function and the presence of severe cystic fibrosis transmembrane conductance regulator mutations are predisposing factors for the development of PEM.

Association of lower airway inflammation with physiologic findings in young children with cystic fibrosis

The relationship between lower airway markers of inflammation and infection with physiologic findings is poorly understood in young children with cystic fibrosis (CF). The goal of this study was to evaluate the association of bronchoalveolar lavage fluid (BALF) markers of infection and inflammation, including mediators linked to airway remodeling, to infant lung function values in young children with CF undergoing clinically indicated bronchoscopy. Plethysmography and the raised volume rapid thoracoabdominal compression (RVRTC) technique were performed in 16 sedated infants and young children with CF prior to bronchoscopy. BALF was collected and analyzed for pathogen density, cell count, % neutrophils, transforming growth factor beta 1 (TGF-beta(1)), matrix metalloproteinases (MMP), and interleukin-8 (IL-8). There was a significant direct correlation between functional residual capacity (FRC), the ratio of residual volume to total lung capacity (RV/TLC) and FRC/TLC with % neutrophils (P < 0.05). Forced expiratory flows were inversely correlated to % neutrophils (P < 0.01). Lung function parameters did not differentiate those with and without lower airway infection; however, pathogen density directly correlated with FRC and inversely correlated with flows (P < 0.05). In a subset of the population, MMP-2 directly correlated with RV/TLC and inversely correlated with flows (P < 0.05) and TGF-beta(1) directly correlated with FRC (P < 0.05). Results from this study suggest that lower airway inflammation as well as mediators linked to airway remodeling play an active role in pulmonary deterioration in CF infants and young children undergoing clinically indicated bronchoscopy.

Longitudinal assessment of lung function from infancy to childhood in patients with cystic fibrosis

Infant pulmonary function testing (IPFT) has become an important clinical tool for the evaluation of lung function in infants with Cystic Fibrosis (CF); however, it is still unclear whether lung function in infancy is predictive of lung function later in life. We hypothesized that measures of airflow obstruction by IPFT would correlate strongly with lung function by conventional spirometry later in childhood. A retrospective analysis was performed of all CF infants studied with IPFT at the University of Minnesota Children's Hospital between September 1994 and March 2003. A total of 41 patients underwent IPFT and had valid spirometry results available at age 6 or later. IPFT values, such as I:E ratio, respiratory rate, tidal volume, and T(ptef)/T(e), were calculated from tidal breathing loops. Passive respiratory system mechanics, which included C(rs), R(rs), and tau(rs), were measured by the single breath end-inspiratory occlusion technique. Forced expiratory flows, including V(max)FRC, FVC, FEF(50), and FEF(75), were obtained by rapid thoracic compression and included a full vital capacity maneuver by the multiple inflation method. FRC measurements were calculated from data obtained via nitrogen washout in a subset of patients. In addition, information on age at diagnosis and results of oropharyngeal (OP) cultures at diagnosis and on subsequent visits was recorded. Standard spirometry was performed in all patients starting at age 5. The first valid flow-volume loop after age six was selected for analysis. Significant correlations were observed for the R(rs) and the FEF(50) by IPFT and the FEV(1) and the FEF(25-75) by standard spirometry (r > 0.4 and P < 0.03 for all correlations). These correlations were the strongest for those IPFT measurements obtained within 1 month of diagnosis and when R(rs) was expressed as sG(rs). The correlations observed were independent of the effects of age at diagnosis, gender and presence of Pseudomonas in oropharyngeal cultures at the time of diagnosis. Mean R(rs) declined from 0.050 to 0.027 cm H(2)O/ml/sec with treatment (P < 0.0001). There were no other significant associations found between other IPFT values measured and FEV(1) by spirometry. Measures of airflow obstruction on IPFT, specifically R(rs), sG(rs), and FEF(50), were strongly correlated with future lung function. IPFT measurement of R(rs) in addition to forced expiratory flows may help select patients at the greatest risk of early lung function decline. This study supports the use of R(rs) as a surrogate variable to help assess the impact of early therapies in CF.