Acceleration of lung disease in children with cystic fibrosis after Pseudomonas aeruginosa acquisition

As part of the ongoing Wisconsin Cystic Fibrosis (CF) Neonatal Screening Project, we had the unique opportunity to study the longitudinal relationship between Pseudomonas aeruginosa (Pa) acquisition and infection and developing lung disease in children with CF. The primary objective was to determine whether acquisition of Pa was associated with a measurable change in the progression of lung disease. Two outcome measures were used to study 56 patients who were diagnosed through newborn screening: 1) Wisconsin additive chest radiograph score (WCXR), based on the average of scores from a pulmonologist and a radiologist, and 2) the highest forced expired volume in 1 sec (FEV(1))/forced vital capacity (FVC) ratio. We used two measures of Pa acquisition: 1) time of first positive protocol-determined oropharyngeal (with cough) culture, and 2) the magnitude of antibody titer detected by ELISA assays, using as antigen a crude cell lysate, purified exotoxin A, or an elastase toxoid prepared from three Pa strains. Other predictor variables included age, pancreatic status, height-for age, and weight-for-age-percentiles. The best regression model for predicting changes in the WCXR included time to first positive culture and antibody titer for Pa elastase. Prior to Pa acquisition, WCXR worsened by 0.45 points/year (P > 0.25); after Pa acquisition, the rate of worsening increased significantly (P < 0.001) to 1.40 points/year. Each antibody titer level (log base 2) increased the score by 0.48 points (P < 0.001). The best regression model for predicting change in the FEV(1)/FVC included only time to first positive culture. Prior to Pa acquisition, the FEV(1)/FVC ratio declined by 1.29%/year; after Pa infection, the rate of decrease significantly accelerated to 1.81%/year (P = 0.001). Our data show that Pa acquisition is associated with declining pulmonary status in children with CF, and that this effect is probably gradual rather than precipitous. Because these patients were diagnosed and treated aggressively, our estimates of the effects of Pa acquisition may be conservative. We also conclude that the WCXR appears to be more sensitive than FEV(1)/FVC in detecting early changes in lung disease associated with CF.     

Regional differences in the evolution of lung disease in children with cystic fibrosis

Progression of lung disease is a major event in children with cystic fibrosis (CF), but regional differences in its evolution are unclear. We hypothesized that regional differences occur beginning in early childhood. We examined this issue by evaluating 132 patients followed in the Wisconsin Neonatal Screening Project between 1985 and 2010. We scored chest X-rays obtained every 1-2 years with the Wisconsin chest X-ray system, in which we divided the lungs into quadrants, and gave special attention to ratings for bronchiectasis (BX) and nodular/branching opacities. We compared the upper and lower quadrant scores, and upper right and left quadrant scores, as patients aged using a multivariable generalized estimation equation (GEE) model. We did a confirmatory analysis for a subset of 81 patients with chest computerized tomography (CT) images obtained in 2000 and scored using the Brody scoring system. The chest X-ray analysis shows that the upper quadrants have higher BX (P<0.001) and nodular/branching opacities (P<0.001) scores than the lower quadrants. CT analysis likewise reveals that the upper quadrants have more BX (P=0.02). Patients positive for mucoid PA showed significantly higher BX scores than patients with non-mucoid PA (P=0.001). Chest X-ray scoring also revealed that the upper right quadrant has more BX (P<0.001) than the upper left quadrant, and CT analysis was again confirmatory (P<0.001). We conclude that pediatric patients with CF develop more severe lung disease in the upper lobes than the lower lobes in association with mucoid PA infections and also have more severe lung disease on the right side than on the left side in the upper quadrants. A variety of potential explanations such as aspiration episodes may be clinically relevant and provide insights regarding therapies.     

Antibody response to Pseudomonas aeruginosa in children with cystic fibrosis

Cystic fibrosis (CF) is the most frequent life threatening autosomal recessive disease in white subjects. The primary cause of morbidity and mortality in children with CF is chronic pulmonary infection, mainly caused by Pseudomonas aeruginosa. The purpose of this study was to assess the value of the measurement of antibodies to P. aeruginosa in diagnosing lung infection by the bacteria in CF patients. We assessed P. aeruginosa antibody titers in CF patients from Rio de Janeiro, Brazil, using cell lysate antigens as well as recombinant PcrV, a Type III Secretion System protein. Sputum (more than 70% of the specimens) or oropharyngeal swabs were obtained whenever patients were regularly followed for their pulmonary disease. Blood samples were obtained with an average interval of 6 months for a period of 2 years. The ELISA cut‐offs were assigned as the positive 95% confidence interval of the mean antibody levels from non‐fibrocystic controls. Our data showed that most CF patients (81%) of whom were not chronically infected by P. aeruginosa (Groups I and II), had their first serology positive for rPcrV. Cell‐lysate ELISA was able to detect P. aeruginosa antibodies before positive culture in the first serum sample of 44% of the patients from Groups I and II. When serum reactivity to rPcrV and cell lysate were combined, 94% of CF patients from Groups I and II (n = 16) had the first serology positive for P. aeruginosa over a mean time of 20 months before the first isolation of P. aeruginosa. In conclusion, longitudinal P. aeruginosa serology should become part of respiratory care follow‐up, in conjunction with other lung parameter functions. Pediatr Pulmonol. 2009; 44:392–401. © 2009 Wiley‐Liss, Inc.     

Lung function in 3-5-year-old children with cystic fibrosis

It is well established that the lung disease of CF can occur early in life and may progress through the preschool years when accurate lung function assessment has been challenging to perform. We hypothesized that respiratory inductive plethysmography (RIP) and spirometry could be effectively performed in 3-6-year-old children and could be used to assess both longitudinal changes in lung function and the acute changes that occur during exacerbation of pulmonary disease. Both RIP and spirometry were equally feasible; however, the success rate for spirometry gradually increased with age to become higher than that for RIP in the 6-year-old subjects. Forty-four subjects were studied longitudinally and demonstrated significant increases in FVC, FEV(1), and FEV(0.5), but not in FEF(25-75) or RIP variables. There were significant differences in FVC, FEV(1), and phase angle (a measure of thoracoabdominal asynchrony) during exacerbations of lung disease. Although both RIP and spirometry were able to show differences in lung function in subjects with acute clinical worsening, spirometry was more robust in demonstrating change in lung function longitudinally and in children who had an exacerbation of lung disease.     

Lung function testing in preschool‐aged children with cystic fibrosis in the clinical setting

In cystic fibrosis (CF) lung function testing is a means of monitoring progression of lung disease. The preschool years have often been referred to as the “silent years” due to the previous lack suitable measures of lung function testing in this age group. This review outlines the various techniques of lung function testing in preschool children with CF in the clinical setting. This includes measures requiring tidal breathing including the forced oscillation technique, the interrupter technique, plethysmography, and multiple breath washout, as well as spirometry that requires respiratory maneuvers. We describe the feasibility and variability of different lung function methods used in preschoolers and report measurements made during tidal breathing have greater feasibility, although greater variability compared to spirometry. We also report associations with lung function and markers of CF lung disease. In the preschool age group measurements made during tidal breathing may be more appropriate in the clinic setting than those that require a higher degree of cooperation and specific respiratory maneuvers.maneuvers. Pediatr Pulmonol. 2010; 45:419–433. © 2010 Wiley‐Liss, Inc.     

Interpretation of lung function in infants and young children with cystic fibrosis

The last decade has seen a significant advance in understanding about early lung disease in cystic fibrosis (CF). As studies that have measured lung function in preschool years are conducted in association with surveillance of infection, inflammation and early structural changes, and emerging longitudinal data become available, a better insight into the very early onset and nature of such lung disease is emerging. Interventions during the preschool years are increasingly viewed as being crucial to delaying and minimizing disease progression as this is the most important period of postnatal life in terms of lung development and airway remodelling. Lung function measurement in CF is potentially an important assessment tool and is used in routine clinical practice in several centres already. Results of studies from lung function tests that, on the basis of their underpinning physiology, are viewed as being best suited currently for the early detection of lung disease in CF are reviewed.     

Longitudinal evaluation of bronchopulmonary disease in children with cystic fibrosis

Children with cystic fibrosis (CF) develop bronchopulmonary disease at variable ages. Determining the epidemiology of chronic lung disease and quantifying its severity, however, have been difficult in infants and young children. As part of the Wisconsin CF Neonatal Screening Project, we were presented with an ideal opportunity to assess longitudinally the evolution of symptoms, signs, and quantitative measures of CF respiratory disease. After newborn screening test results led to early recognition, 64 patients diagnosed at a median age of 6.71 weeks were enrolled and studied systematically at a median age of 11.3 years to obtain clinical information, chest radiographs, and pulmonary function tests. Our observations revealed that a frequent cough by history is evident by 10.5 months of age in half the patients. Quantitative chest radiology (CXR scoring) demonstrated that potentially irreversible abnormalities are present in half the children by 2 years. The severity of Wisconsin and Brasfield CXR scores increased in association with respiratory infections. Longitudinal progression of Wisconsin CXR scores was related to age (P < 0.001), pancreatic insufficiency (P = 0.005), and respiratory secretion cultures positive for Staphylococus aureas (P = 0.039). In contrast, serial spirometry showed limited sensitivity, as did lung volume determinations; neither was satisfactory as repeated measures with acceptable quality control until after 7 years of age. Time to event analyses revealed that half the patients had % predicted FEF(25-75) and FEV(1)/FVC values greater than 80% until 10.7 and 9.9 years, respectively. We conclude that of the methods evaluated, quantitative chest radiology is currently the best procedure for frequent assessment of bronchopulmonary disease in CF, and that radiographic progression is evident in approximately 85% of patients by 5 years of age. Our results also suggest that bronchiectasis and other radiographic evidence of chronic infection are apparent prior to airways obstruction in young CF patients.     

Early pulmonary inflammation and lung damage in children with cystic fibrosis

Individuals with cystic fibrosis (CF) suffer progressive airway inflammation, infection and lung damage. Airway inflammation and infection are present from early in life, often before children are symptomatic. CF gene mutations cause changes in the CF transmembrane regulator protein that result in an aberrant airway microenvironment including airway surface liquid (ASL) dehydration, reduced ASL acidity, altered airway mucin and a dysregulated inflammatory response. This review discusses how an altered microenvironment drives CF lung disease before overt airway infection, the response of the CF airway to early infection, and methods to prevent inflammation and early lung disease.     

Association of body composition and lung function in children with cystic fibrosis

Survival in cystic fibrosis has improved significantly in the last 30 years, with major therapeutic goals of delaying the progressive loss of pulmonary function and maintaining normal growth. Dual-energy X-ray absorptiometry (DEXA) was performed in children with cystic fibrosis (CF) to assess both bone mineral density and body composition. We hypothesised that there would be an association between body composition and pulmonary function in children with CF. Fifty subjects with CF (28 males), mean age 12.7 years, participated in the study. Body composition was determined by DEXA. Body mass index (BMI) was calculated from the ratio of weight/height2 (kg/m2). Lung function was assessed by spirometry. Most patients (78%) had mild lung disease. The mean forced expired volume in 1 sec percent predicted (FEV1% predicted) for the 50 patients was 79.2% (range, 24-117%). There was a strong association between FEV1% predicted and BMI (R=0.59, P=0.0001). Fat-free mass had positive association with pulmonary function tests (R=0.30, P=0.03). Although fat mass showed a positive correlation with pulmonary function, this association did not reach statistical significance. In our group of children with CF and mild lung disease, pulmonary function was more strongly associated with BMI than with fat and fat-free mass.     

Correlation between digital clubbing and pulmonary function in cystic fibrosis

The correlation between digital clubbing and certain pulmonary function derangements (hypoxemia and FEV(1)) was previously described. However, the relationship between digital clubbing and other measures of pulmonary function or the presence of liver disease in patients with cystic fibrosis (CF) is poorly defined. Hence we compared the digital clubbing index (CI: ratio of distal phalangeal depth to interphalangeal depth) of 100 patients with CF (43 males, 57 females; mean age, 15.7 +/- 7.3 years) with that of 100 age- and gender-matched healthy controls. Digital clubbing was defined as a CI > or = 1.00 (mean + 2.6 SD; 99% of normal subjects). The CI and its relationship to pulmonary function and to liver disease was then evaluated in the CF patients. Digital clubbing was present in 75/100 (75%) of CF patients but was absent in all controls (P < 0.0001). In CF patients, CI was inversely correlated with PaO(2) (r = -0.555; P < 0.001), FEV(1) (r = -0.499; P < 0.001), and FEF(25-75%) (r = -0.404; P < 0.001), and was positively correlated with RV (r = 0.285; P < 0.05) and the slope of phase 3 of single-breath nitrogen washout (SP3N(2)) (r = 0.532; P < 0.01). There was no significant correlation between CI and age (r = 0.020; P = 0.84), TLC (r = -0.097; P = 0.34), PaCO(2) (r = 0.167; P = 0.10), or history of liver disease (P = 0.08). We conclude that in CF, the degree of digital clubbing is related to degree of hypoxemia, airways obstruction, hyperinflation, and nonuniformity of ventilation.     

Antibiotic treatment of initial colonization with Pseudomonas aeruginosa postpones chronic infection and prevents deterioration of pulmonary function in cystic fibrosis

Chronic pulmonary infection with Pseudomonas aeruginosa (PA) develops in most patients with cystic fibrosis (CF) and is associated with a poor prognosis. Much effort has been directed toward treating the chronic infection, but it is almost impossible to eradicate it once established; therefore, prevention is preferable. Since 1989 CF patients at the Danish CF Center in Copenhagen have been treated with an intensive three-step-protocol consisting of colistin inhalations and oral ciprofloxacin at the time of initial PA colonization. This study compares 48 patients treated according to this intensive protocol with 43 historic controls. The study was carried out over 44 months and included 218 patient-years. Only 16% of the treated patients developed chronic PA infection after 3 1/2 years compared with 72% of the control patients (Kaplan Meier estimate, P < 0.005, log rank test). This indicates that aggressive treatment prevented or delayed chronic PA infection in 78% of the patients for 3 1/2 years. Furthermore, aggressive treatment maintained or increased pulmonary function (forced vital capacity and forced expiratory volume in 1 second in percent of predicted values) during the year after inclusion compared with the control group, in which pulmonary function declined (P < 0.01, Mann-Whitney test). Although some of the treated patients eventually developed chronic PA infection, these patients had significantly better pulmonary function at the onset of chronic PA infection compared with control patients (P < 0.001, Mann-Whitney test). When the different steps in the intensive three-step-protocol were analyzed, there was a trend suggesting that 3 months of high-dose treatment with colistin inhalation and oral ciprofloxacin produced the best results in terms of postponement or prevention of chronic PA infection (P < 0.05). Pediatr. Pulmonol. 1997; 23:330–335. © 1997 Wiley-Liss, Inc.