Changing epidemiology of Pseudomonas aeruginosa infection in Danish cystic fibrosis patients (1974-1995).

Recurrent and chronic lower airway infection with Pseudomonas aeruginosa (PA) is an important component of cystic fibrosis (CF) pulmonary disease. Different modes of treatment and control of CF patients have been introduced at the Copenhagen CF Centre over the past 20 years and have been associated with improved survival. Treatment consisted of: 1) elective antibiotics for 14 days every 3 months to patients with chronic PA infection (started in 1976), 2) cohort isolation to prevent cross-infection (patients with PA were separated from patients without PA, starting in 1981); and 3) early intensive treatment with inhaled colistin and oral ciprofloxacin from time of initial PA colonization (started in 1989). The aim of the present study was to evaluate the impact of each of these interventions on the changes in the epidemiology of PA. Based on monthly cultures of lower airway secretions in each CF patient seen during 1974-1995, significant changes in the incidence and prevalence of the PA infection were found. The monthly prevalence of chronic PA increased significantly (P < 0.0001) from below 40% before 1976 to above 60% in 1980, which was found to be due to cross-infection among the CF patients after introduction of elective antibiotic courses in 1976. To deal with this problem, cohort isolation was introduced in 1981, and since then the monthly point prevalence of chronic PA decreased slowly until 1989 (P < 0.0001), when early intensive treatment from initial PA colonization was introduced; this was associated with a further decrease in point prevalence to 45% in 1995 (P < 0.005). The annual incidence of chronic PA infection also decreased significantly (P < 0.01) from 16% to below 2% after introduction of cohort isolation and early intensive treatment from initial PA isolation. Furthermore, the time from acquisition of first PA to development of chronic PA infection increased significantly, from approximately 1 year to almost 4 years after introduction of cohort isolation (P < 0.0001). After introduction of early intensive treatment, the probability of still not having developed chronic PA infection 7 years after the first isolation of PA was above 80% (P < 0.0001). In conclusion, the introduction of cohort isolation and early intensive treatment following the initial isolation of PA resulted in a reduced incidence and prevalence of chronic PA infection. We are not aware of other studies showing a decreasing prevalence of chronic PA infection, as survival of CF patients has increased.     

Longitudinal assessment of Pseudomonas aeruginosa in young children with cystic fibrosis

Pseudomonas aeruginosa lung infection is an important cause of morbidity and mortality in cystic fibrosis (CF). Longitudinal assessment of the phenotypic changes in P. aeruginosa isolated from young children with CF is lacking. This study investigated genotypic and phenotypic changes in P. aeruginosa from oropharynx (OP) and bronchoalveolar lavage fluid (BALF) in a cohort of 40 CF patients during the first 3 years of life; antibody response was also examined. A high degree of genotypic variability was identified, and each patient had unique genotypes. Early isolates had a phenotype distinct from those of usual CF isolates: generally nonmucoid and antibiotic susceptible. Genotype and phenotype correlated between OP and BALF isolates. As determined by culture, 72.5% of patients demonstrated P. aeruginosa during their first 3 years. On the basis of combined culture and serologic results, 97.5% of patients had evidence of infection by age 3 years, which suggests that P. aeruginosa infection occurs early in CF and may be intermittent or undetectable by culture.     

Importance of controlling drug-resistant Pseudomonas aeruginosa infection: experience from lung transplantation in a cystic fibrosis case

Cystic fibrosis (CF) is rare in Japan. We encountered a CF case with drug-resistant Pseudomonas aeruginosa infection and successfully performed lung transplant from living related donors. A combination of beta-lactams and aminoglycosides for drug-resistant P. aeruginosa infection was administered before lung transplantation. Intravenous colistin was also used immediately before and after transplant surgery. Gram staining of respiratory specimens was performed every day after surgery and it was useful in monitoring infection status. Strict monitoring of infections by the Gram staining and culture of respiratory specimens is considered to be effective in preventing lower respiratory infection in lung transplantation.     

Mucoid Pseudomonas aeruginosa is a marker of poor survival in cystic fibrosis.

The aim of this study was to assess the prognostic significance of mucoid and non-mucoid isolates of Pseudomonas aeruginosa (muPs and non-muPs) from the sputa of patients with cystic fibrosis (CF). Eighty-one children with CF who coughed up sputum daily were recruited and followed over 12 months with frequent sputum cultures. At the end of this observation period they were classified to one of three age-matched groups. In 50 mPs was isolated on one or more occasions; 19 grew non-muPs but not muPs, and 12 grew no isolates of Ps aeruginosa. These 81 children and adolescents were followed for a further 8 years or until they died. Twenty-one (42%) of the muPs patients died compared with two (11%) of the non-muPs and one (8%) of the no Ps patients (P less than 0.01). Stepwise regression indicated that forced expiratory volume in 1 second (FEV1) had the main predictive effect but that age, Shwachman score and muPs also had a predictive effect. Identification of mucoid forms of Ps aeruginosa is an unfavorable prognostic factor but the isolation of non-mucoid strains does not appear to be any more important than the isolation of other common respiratory pathogens.     

Bacteraemia and fungaemia in adults with cystic fibrosis

The incidence of bacteraemia and fungaemia was determined in 29 adults with cystic fibrosis (CF) during 50 consecutive admissions to hospital for management of infective exacerbations of pulmonary disease. Blood was drawn for aerobic, anaerobic and fungal cultures from all patients who were febrile on admission or who became febrile during treatment. The population included eight patients who had indwelling venous access systems in situ. The overall incidence of positive blood cultures in febrile patients was 3.5% [95% confidence interval (C.I.), 1-6%]. We recorded one case of Pseudomonas aeruginosa bacteraemia and two cases of Candida albicans fungaemia. The patient with P. aeruginosa bacteraemia died 5 days after isolation of the organism from her blood. The two patients with C. albicans bacteraemia had totally implantable venous access systems (TIVAS) in situ and both recovered following appropriate therapy. These observations suggest that bacteraemia is rare in patients with CF but that there is a significant risk of fungaemia in a susceptible minority. The implications of these findings, as they relate to management of infections and care of indwelling catheters in such patients, are discussed.     

A randomised clinical trial of nebulised tobramycin or colistin in cystic fibrosis.

Chronic infection with Pseudomonas aeruginosa is associated with progressive deterioration in lung function in cystic fibrosis (CF) patients. The purpose of this trial was to assess the efficacy and safety of tobramycin nebuliser solution (TNS) and nebulised colistin in CF patients chronically infected with P. aeruginosa. One-hundred and fifteen patients, aged > or = 6 yrs, were randomised to receive either TNS or colistin, twice daily for 4 weeks. The primary end point was an evaluation of the relative change in lung function from baseline, as measured by forced expiratory volume in one second % predicted. Secondary end points included changes in sputum P. aeruginosa density, tobramycin/colistin minimum inhibitory concentrations and safety assessments. TNS produced a mean 6.7% improvement in lung function (p=0.006), whilst there was no significant improvement in the colistin-treated patients (mean change 0.37%). Both nebulised antibiotic regimens produced a significant decrease in the sputum P. aeruginosa density, and there was no development of highly resistant strains over the course of the study. The safety profile for both nebulised antibiotics was good. Tobramycin nebuliser solution significantly improved lung function of patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa, but colistin did not, in this study of 1-month's duration. Both treatments reduced the bacterial load.     

Genotypic characterization of Pseudomonas aeruginosa strains recovered from patients with cystic fibrosis after initial and subsequent colonization

Chronic infection by Pseudomonas aeruginosa (PA) in patients with cystic fibrosis (CF) is preceded by a period of colonization and acute infection. Early aggressive antibiotic treatment of initial colonisation may prevent or at least delay chronic pulmonary infection. We initiated treatment with a combination of IV beta-lactam tobramycin, followed by nebulized colistin when PA was first isolated from patients with CF. Subsequent serial PA isolates obtained from these colonized CF patients were characterized by means of molecular methods to determine whether they were genetically related to the initial strain. Initial colonization was eradicated in all 19 patients. All patients reacquired PA within 3-25 months during the 3 years of follow-up. Fourteen patients acquired a new PA strain with a distinct genotypic profile, suggesting a new source of contamination. Five patients had two PA isolates with identical genotypes, suggesting either previous undetected respiratory tract colonization or a persistent environmental source of contamination.     

Effect of continuous antistaphylococcal therapy on the rate of P. aeruginosa acquisition in patients with cystic fibrosis

SUMMARY. Continuous therapy with antistaphylococcal antibiotics is advocated by some cystic fibrosis (CF) centers, but it is unclear whether this strategy favors early colonization with P. aeruginosa. We used the data base for the German Centers of the European Registry for Cystic Fibrosis (ERCF) to assess the effect of continuous antistaphyloccocal therapy on the rate of P. aeruginosa acquisition in CF patients. Patients included in this analysis had to be < 18 years of age, P. aeruginosa-negative prior to entry in the ERCF, and to have had at least 2 additional P. aeruginosa-negative respiratory cultures while followed in the ERCF. Of the 639 patients fulfilling these criteria, 48.2% received continuous antistaphyloccocal therapy, 40.4% intermittent antibiotic therapy, and 11.4% no antibiotic therapy. There were no differences between the groups in body mass index, as well as forced vital capacity (FVC) and forced expired volume in 1 sec (FEV(1)) at baseline. The rate at which patients acquired positive respiratory cultures for Staph. aureus was significantly lower in the group receiving continuous antistaphyloccocal antibiotic therapy than in those not receiving such therapy. Patients receiving continuous antistaphyloccocal antibiotic therapy had a significantly higher rate of P. aeruginosa acquisition compared to patients receiving only intermittent or no antibiotic therapy. This difference was especially apparent for children younger than age 6 years. We conclude that continuous therapy with antistapyloccocal antibiotics directed against Staph. aureus increases the risk of colonization with P. aeruginosa. How this affects the clinical outcome of these patients remains to be determined.     

Quantitative proteomic analysis indicates increased synthesis of a quinolone by Pseudomonas aeruginosa isolates from cystic fibrosis airways

The opportunistic bacterial pathogen Pseudomonas aeruginosa colonizes airways of individuals with cystic fibrosis (CF) with resultant chronic destructive lung disease. P. aeruginosa adaptation to the CF airway includes biofilm formation and antibiotic resistance. Isolates from asymptomatic individuals in the first 3 years of life have unique characteristics, suggesting that adaptation occurs before clinical symptoms. One defined early adaptation is expression of a specific proinflammatory lipopolysaccharide (LPS) that is associated with antimicrobial peptide resistance. This CF-specific LPS is induced when P. aeruginosa is grown in medium that is limited for magnesium. Therefore, qualitative and quantitative proteomic approaches were used to define 1,331 P. aeruginosa proteins, of which 145 were differentially expressed on limitation of magnesium. Among proteins induced by low magnesium were enzymes essential for production of 2-heptyl 3-hydroxy 4-quinolone, the Pseudomonas quinolone signal (PQS), which interacts with the homoserine lactone signaling pathway. Measurement of PQS in P. aeruginosa isolates from asymptomatic children with CF indicated that strains with increased synthesis of PQS are present during early colonization of CF patient airways.     

Risk factors for initial acquisition of Pseudomonas aeruginosa in children with cystic fibrosis identified by newborn screening

The objective of this study was to identify risk factors for initial detection of Pseudomonas aeruginosa (P. aeruginosa) in children with cystic fibrosis (CF) identified by newborn screening. Life history data on 180 patients, collected prospectively in a follow-up study of infants and children diagnosed with CF, were examined for factors associated with the initial detection of P. aeruginosa ascertained by oropharyngeal cultures. Univariate and multivariate Cox proportional hazards regression analyses were used to assess the effect of baseline and time-varying covariates on age at first positive culture for P. aeruginosa. Seventy-nine patients (44%) had at least one culture positive for P. aeruginosa during the study. The median age of detection was 8.1 years (95% CI, 7.0, 10.0). Median length of follow-up was 4.1 years, ranging from 0.2-15.5 years. Multivariate Cox regression analysis identified female gender (RR, 1.85; 95% CI, 1.14, 3.01), the DeltaF508 homozygous genotype (RR, 2.23; 95% CI, 1.30, 3.80), and S. aureus isolations (RR, 1.30; 95% CI, 1.11, 1.52) to be independently associated with acquisition of P. aeruginosa. Other marginally independent associations were found with days hospitalized and increased height. We conclude that female gender, homozygous DeltaF508 mutation, and S. aureus isolations are important risk factors for early P. aeruginosa detection in children with CF identified through newborn screening.     

Renal impairment in cystic fibrosis patients due to repeated intravenous aminoglycoside use

Although there are reports of cases of acute renal failure occurring in cystic fibrosis (CF) patients, usually in association with the use of nephrotoxic antibiotic therapy, there have been no studies of renal function in this patient group. We hypothesized that long-term use of intravenous (IV) nephrotoxic antibiotics (aminoglycosides and colistin sulphomethate) may contribute to renal disease in CF patients. In a prospective study, we assessed creatinine clearance as an index of renal function with two techniques (24-hr urine collections and the Cockroft-Gault formula) in a group of 80 stable adult CF outpatients chronically infected with Pseudomonas aeruginosa but with no history of preceding renal disease. Using a multiple linear regression model, we evaluated their renal function in terms of their lifetime IV use of aminoglycosides and colistin. Between 31% (Cockroft-Gault formula method) and 42% (24-hr urine collection method) of patients had a creatinine clearance below normal range. Using either method, there was a strong correlation between aminoglycoside use and diminishing renal function (r=- 0.32, P=0.0055), which was potentiated by the coadministration of colistin (r=- 0.42, P <0.0002). However, there was no correlation with colistin when used in combination with other antibiotics alone (r=0.18, P=NS). Repeated IV aminoglycoside use in CF is associated with long-term renal damage. Although this effect is potentiated by colistin, colistin on its own in moderate doses does not appear to be nephrotoxic. IV aminoglycosides should be used cautiously in CF patients, with regular monitoring of renal function.     

Reduction in prevalence of chronic Pseudomonas aeruginosa infection at a regional pediatric cystic fibrosis center

Various management strategies were introduced at the Leeds Regional Cystic Fibrosis (CF) Unit in an attempt to reduce the prevalence of chronic Pseudomonas aeruginosa respiratory infection, previously thought to be inevitable in most children with CF. These included neonatal screening (1975), regular microbiological monitoring (1975), early antibiotic treatment of first isolations of P. aeruginosa (1985), intensive intravenous antibiotic treatment where nebulized antibiotics failed to eradicate P. aeruginosa (1988), and separate clinics for patients chronically infected with P. aeruginosa and uninfected patients (1991). The aim of this study was to assess the impact of these interventions. All 232 patients receiving full-time care at the Leeds Paediatric CF Centre during the period January 1990-December 2000 were categorized into four groups: never grown P. aeruginosa; free of P. aeruginosa for at least 1 year; intermittent grower of P. aeruginosa with 50% of months with samples positive for P. aeruginosa over the previous 12 months. The yearly prevalence of patients having chronic P. aeruginosa infection fell significantly during the study, from 24.5% in 1990 to 18.1% in 2000 (P < 0.05), despite an increase in mean age of patients from 7.73 to 9.42 years. The number of patients aged less than 11 years who had chronic P. aeruginosa infection fell from 23.8% in January 1990 to only 4.3% by December 2000. The annual incidence and mean age of first acquisition of P. aeruginosa did not alter significantly. In conclusion, antipseudomonal management strategies were associated with both reduced prevalence, and an increase in the mean age of onset of chronic P. aeruginosa infection.     

Diagnostic value of serum antibodies in early Pseudomonas aeruginosa infection in cystic fibrosis patients

Specific serum antibodies could be helpful in defining the status of Pseudomonas aeruginosa infection as well as the response to early intervention treatment in patients with cystic fibrosis (CF). We used 1,791 serum samples from 375 European CF patients with known respiratory microbiology status to define titers of P. aeruginosa antibodies directed against alkaline protease (AP), elastase (ELA), and exotoxin A (ExoA). Pseudomonas antibody titers were also measured in a separate cohort of 56 patients undergoing antibiotic treatment for eradication of P. aeruginosa. At a specificity of 97.5%, the sensitivity was highest for antibodies against AP (85.4%), followed by ELA (76.2%) and ExoA (72.0%). AP, ELA, or ExoA antibody titers were significantly higher (P < 0.001) in patients chronically infected with P. aeruginosa compared to patients with negative cultures. The sensitivity of the combined three ELISAs was higher than that for any single ELISA alone. Based on the newly defined cut-off levels, positive serum antibody titers against at least one of the three antigens were present in 43% of patients with new onset of P. aeruginosa infection. Longitudinal assessment of antibody titers assessed before and after inhaled antibiotic therapy in patients with first P. aeruginosa isolation showed a significant decrease in antibody titers against AP and ExoA in patients clearing P. aeruginosa infection, whereas titers increased in patients in whom antibiotic therapy failed to eradicate the organism. Antibody testing against AP, ELA, and ExoA offers high sensitivity and specificity for the presence of P. aeruginosa in respiratory cultures of CF patients. Although serum antibody titers are on average low at the time of first P. aeruginosa isolation from respiratory specimens, they may be useful to monitor response to therapy. However, because variability between patients is considerable, treatment decisions should not be based on P. aeruginosa antibody levels alone.     

Bronchial constriction and inhaled colistin in cystic fibrosis

STUDY OBJECTIVE: Inhaled colistin is used for the treatment of Pseudomonas aeruginosa infection in cystic fibrosis (CF) patients despite reports of chest tightness and bronchospasm. The main objective of the study was to assess whether bronchospasm occurred in pediatric CF patients with or without clinical evidence of airway hyperreactivity. DESIGN AND METHODS: A prospective placebo-controlled clinical trial with crossover design was devised using challenge tests with 75 mg colistin in 4 mL saline solution and a placebo solution of the same osmolarity using a breath-enhanced nebulizer for administration. Subjects were recruited as follows: high risk (HR) for bronchospasm due to a personal history of recurrent wheezing, a family history of asthma and/or atopy, or bronchial lability, as demonstrated in pulmonary function tests; or low risk (LR) without these characteristics. RESULTS: The mean FEV(1) (expressed as the mean [+/- SD] fall from baseline) of the HR group (n = 12) fell 12 +/- 9% after placebo was administered, and fell 17 +/- 10% after colistin was administered. For the LR group (n = 8), the mean FEV(1) fell 9 +/- 4% following placebo administration and 13 +/- 8% following colistin administration. There was a greater number of subjects in the HR group compared to the LR group, which had a mean fall in FEV(1) of >/= 15% (p < 0.01) after inhaling colistin. The differences between placebo and colistin therapy in the LR group were not significant. CONCLUSION: The results demonstrated that colistin can cause bronchospasm, particularly in those patients with coexisting CF and asthma.     

Familial concordance of phenotype and microbial variation among siblings with CF

The clinical spectrum of cystic fibrosis (CF) is influenced by the cystic fibrosis transmembrane conductance regulator (CFTR) genotype. However, variable courses of the disease were demonstrated among patients with identical genotypes. Since siblings share identical CFTR mutations and environmental factors, they can serve as a model to assess the effect of modifier genes on disease expression, and also to evaluate cross-infection. The aim of this study was to compare disease expression among siblings with CF. All sibling pairs treated at 7 CF centers in Israel were included in the study. Data were collected from patients' medical charts. Fifty families with at least 2 siblings were identified. As expected, the second-born sibling was diagnosed at an earlier age compared to the first-born. The mode of CF presentation at diagnosis showed significant familial concordance. In the families where the first sibling presented with gastrointestinal manifestations, 79% of the second siblings also presented with gastrointestinal manifestations. When gastrointestinal manifestations were absent in the first sibling, only 12% of the second siblings presented with gastrointestinal manifestations (P < 0.0001). Likewise, when the first sibling presented with respiratory symptoms, 60% of the second siblings presented with the similar symptoms. However, when the first sibling presented without respiratory symptoms, only 12% of the second siblings presented with respiratory symptoms (P < 0.001). Meconium ileus (MI) was present in 20 patients (21%). In 10 families where the first-born sibling had MI, 8 (80%) of the subsequent siblings had MI. On the other hand, in the 39 families where the first-born sibling did not have MI, only 2 (5%) subsequent siblings had MI (P < 0.001). Pancreatic insufficiency (PI) also had high familial concordance (P < 0.0001). Percentile growth for weights and heights and lung function (FVC, FEV(1), and FEF(25-75)) at ages 7 and 10 years were similar between siblings. P. aeruginosa grew from sputum in 89% of our study patients. When P. aeruginosa was isolated from the first-born patient, 91% of the second siblings were also positive for P. aeruginosa, whereas when the initial sibling was not a carrier of P. aeruginosa, only 50% of subsequent siblings were positive (P < 0.0001). This familial concordance was not observed for S. aureus. By contrast, the age of first isolation of P. aeruginosa and S. aureus was significantly earlier in the second sibling than in the first for the two bacteria: 10.3 +/- 5.1 vs. 7.3 +/- 5.2 years (P < 0.05) for P. aeruginosa, and 11.5 +/- 5.4 years vs. 6.8 +/- 5.1 years (P < 0.05) for S. aureus. CF siblings tend to share similar phenotypes that are not mutation-dependent. The lack of variability between siblings in mode of initial CF presentation, rates of MI, pulmonary function, and nutritional status supports the role of modifier genes in the determination of these factors.     

Transplantation for cystic fibrosis: outcome following early liver transplantation

BACKGROUND AND AIM: Life expectancy in patients with cystic fibrosis (CF) has recently improved due to numerous factors, including a multidisciplinary approach to their management. Prolonged survival may have led to an increasing impact of liver disease on the prognosis of CF patients. The aim of this study was to assess the role of liver transplantation in patients with CF. METHODS: The factors influencing outcome in 24 patients (15 adults and nine children) with CF who have received single liver transplantation, triple heart-lung-liver transplantation (tx) or died while being assessed for triple grafting, were analyzed. RESULTS: Median age at tx in single liver recipients (13 years) was lower than in triple graft recipients (21 years) and those who died (23 years). All patients who received single liver tx made an excellent recovery, including significant improvement of their respiratory function (mean forced vital capacity (FVC) increased from 61% before transplantation to 82% of expected, 6-9 months after tx). Four out of five patients who received triple tx died (0-2 months) after operation. On the basis of our retrospective review, we propose modifications to an existing scoring system for liver tx assessment in CF by scoring additional points for elevated white blood count, bilirubin, and impaired pulmonary function. These changes will need to be evaluated prospectively to confirm their predictive value. CONCLUSIONS: Liver transplantation is effective therapy in young patients with cystic fibrosis, portal hypertension and hepatic dysfunction, and is indicated before a critical stage of deteriorating lung function is reached. In patients with both end-stage liver and lung disease, triple tx has a poor prognosis. Pre-emptive liver tx in younger patients with CF not only has a better outcome but improves lung function.     

Nebulized antibiotic therapy: the evidence

The main indications for nebulized antibiotic use are as maintenance therapy for patients with chronic Pseudomonas aeruginosa infection and in treatment protocols aimed at eradicating early P. aeruginosa infection. Daily nebulized antibiotic therapy has been used extensively in Europe for the last 25 years and recently in North America following the introduction of tobramycin solution for inhalation (TSI). The antibiotic is delivered directly to the site of infection, maximizing its efficacy and reducing its potential for toxicity. The efficacy of nebulized antibiotic therapy has been confirmed by meta-analyses of early studies which usually involved only small numbers of patients, and recently by large scale randomized control trials. These studies have shown that regular aerosolized antibiotic treatment results in improved respiratory function, less hospital admissions and respiratory exacerbations, and a significant reduction in the load of P. aeruginosa respiratory tract infection. Concerns about increasing bacterial resistance do not yet seem to have had any clinical impact. Successful eradication of early P. aeruginosa infection has been reported with nebulized colistin (in combination with oral ciprofloxacin), tobramycin and TSI. No advantage has been shown in studies comparing nebulized and intravenous antibiotics versus intravenous antibiotics alone in the treatment of acute respiratory exacerbations. Inhalation of antibiotics may provoke bronchospasm and patients should be assessed before and after treatment prior to continuing long-term therapy at home.     

Multiple-breath washout as a marker of lung disease in preschool children with cystic fibrosis

Sensitive measures of lung function applicable to young subjects are needed to detect early cystic fibrosis (CF) lung disease. Forty children with CF aged 2 to 5 years and 37 age-matched healthy control subjects performed multiple-breath inert gas washout, plethysmography, and spirometry. Thirty children in each group successfully completed all measures, with success on first visit being between 68 and 86% for all three measures. Children with CF had significantly higher lung clearance index (mean [95% CI] difference for CF control 2.7 [1.9, 3.6], p < 0.001) and specific airway resistance (1.65 z-scores [0.96, 2.33], p < 0.001), and significantly lower forced expired volume in 0.5 seconds (-0.49 z-scores [-0.95, -0.03], p < 0.05). Abnormal lung function results were identified in 22 (73%) of 30 children with CF by multiple-breath washout, compared with 14 (47%) of 30 by plethysmography, and 4 (13%) of 30 by spirometry. Children with CF who were infected with Pseudomonas aeruginosa had significantly higher lung clearance index, but no significant difference in other lung function measures, when compared with noninfected children. Most preschool children can perform multiple-breath washout, plethysmography, and spirometry at first attempt. Multiple-breath washout detects abnormal lung function in children with CF more readily than plethysmography or spirometry.     

Affinity constants of naturally acquired and vaccine-induced anti-Pseudomonas aeruginosa antibodies in healthy adults and cystic fibrosis patients.

Naturally acquired anti-Pseudomonas aeruginosa antibody fails to afford protection against repeated P. aeruginosa bronchopulmonary exacerbations in cystic fibrosis (CF) patients. In an effort to explain this phenomenon, the titer and affinity constants of serum anti-lipopolysaccharide (LPS) IgG were determined in five study groups: healthy adults before and after immunization with a polyvalent LPS-based vaccine, healthy noncolonized CF patients before and after immunization, nonimmunized CF patients with significantly elevated anti-LPS antibody titers without documented colonization, recently colonized CF patients before and after immunization, and nonimmunized CF patients chronically colonized with P. aeruginosa. Immunization elicited a significant rise in total anti-LPS immunoglobulin levels and affinity constants in both healthy adults and CF patients. Although chronically colonized patients had elevated levels of total anti-LPS antibody, these antibodies possessed affinities at least 100-fold less than those of vaccine-induced antibodies.