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Risk Factors For Rate of Decline in Forced Expiratory Volume in One Second in Children and Adolescents with Cystic Fibrosis
Abstract
To characterize the rate of decline of forced expiratory volume in 1 second (FEV(1)) in children and adolescents with cystic fibrosis and to identify and compare risk factors associated with FEV(1) decline.
The rate of decline in FEV(1)% predicted over 3 to 6 years in 3 different age groups was determined. Risk factors for decline were identified and compared among and within age groups as a function of disease severity with repeated-measures, mixed-model regression.
Mean (+/-SD) baseline FEV(1)% predicted was 88.4% +/- 20.5% for 6- to 8-year-olds (n = 1811), 85.3% +/- 20.8% for 9- to 12-year-olds (n = 1696), and 78.4% +/- 22.0% for 13- to 17-year-olds (n = 1359). Decline in FEV(1)% predicted/year was -1.12, -2.39, and -2.34, respectively. High baseline FEV(1) and persistent crackles were significant independent risk factors for decline across all age groups. Female sex, Pseudomonas aeruginosa infection, low weight-for-age, sputum, wheezing, sinusitis, pulmonary exacerbations treated with intravenous antibiotics, elevated liver test results, and pancreatic insufficiency were also identified as independent risk factors in some age groups.
This study identifies risk factors for FEV(1) decline in children and adolescents with cystic fibrosis. Clinicians should not be reassured by high lung function, particularly in young children, because this factor, among others, is independently associated with steeper decline in FEV(1).
... 13 Respiratory tract colonization with P. aeruginosa and other bacteria are well-defined entities and well-documented causes of lung function decline in children and adults with cystic fibrosis. [14][15][16][17][18] Although long-term colonization has not been defined in children with tracheostomies, recurrent P. aeruginosa isolation on tracheostomy aspirate cultures has been associated with poor short-term outcomes, including longer hospitalizations and higher readmission rates. 13,19 However, long term outcomes of acute and recurrent bacterial isolation have not been assessed among children with tracheostomies or those with BPD. ...
... This is in contrast to what is known among other populations (i.e., cystic fibrosis, COPD), in which such pathogenic respiratory bacteria has been demonstrated to decrease lung function over time, as directly measured by pulmonary function testing and indirectly measured by disease exacerbation risk. [14][15][16][17][18][25][26][27][28][29][30] This lack of association with ongoing respiratory support among children with tracheostomies is particularly important because it was identified in spite of the fact that children with pathogen identification had far more cultures obtained than their peers without pathogen identification. In additional analysis of what factors do drive untimely respiratory support weaning, not surprisingly, a child's number of complex chronic conditions was associated with continued need for respiratory support in this cohort. ...
Background: While bacteria identification on respiratory cultures is associated with poor short-term outcomes in children with bronchopulmonary dysplasia (BPD) and tracheostomies, the influence on longer-term respiratory support needs remains unknown. Objective: To determine if respiratory culture growth of pathogenic organisms is associated with ongoing need for respiratory support, decannulation, and death at 3 years post-tracheostomy placement in children with BPD and tracheostomies. Methods: This single center, retrospective cohort study included infants and children with BPD and tracheostomies placed 2010-2018 and >1 respiratory culture obtained in 36 months post-tracheostomy. Primary predictor was any pathogen identified on respiratory culture. Additional predictors were any Pseudomonas aeruginosa and chronic P. aeruginosa identification. Outcomes included continued use of respiratory support (e.g., oxygen, positive pressure), decannulation, and death at 3 years post-tracheostomy. We used Poisson regression models to examine the relationship between respiratory organisms and outcomes, controlling for patient-level covariates and within-patient clustering. Results: Among 170 children, 59.4% had a pathogen identified, 28.8% ever had P. aeruginosa , and 3.5% had chronic P. aeruginosa . At 3 years, 33.1% of alive children required ongoing respiratory support and 24.8% achieved decannulation; 18.9% were deceased. In adjusted analysis, any pathogen and P. aeruginosa were not associated with ongoing respiratory support or mortality. However, P. aeruginosa was associated with decreased risk of decannulation (aRR 0.48, 95% CI 0.23-0.98). Chronic P. aeruginosa was associated with lower survival probability. Conclusion : Our findings suggest that respiratory pathogens including P. aeruginosa may not promote long-term respiratory dysfunction, but identification of P. aeruginosa may delay decannulation.
... Because pulmonary complications are responsible for the majority of mortality and morbidity in children with cystic fibrosis (CF), monitoring pulmonary function and detecting declines early are of critical importance (1,2). However, there is still no reliable method or combination of methods for assessing respiratory function. ...
... Pulmonary function testing, sputum culture, lung imaging methods, and scoring systems can be used to assess pulmonary involvement. In the stages when clinical findings can be detected in children, significant deterioration has occurred in pulmonary function tests (2,4). A major reason for this is that the spirometric methods routinely used to measure pulmonary functions require maneuvers that children cannot perform, especially at very young ages (5). ...
... In the short term, PEx commonly result in morbidity, increased treatment burden, and decreased quality of life [5]. Over the longer term, PEx requiring hospitalization are associated with accelerated lung disease progression [6,7] and increased mortality risk [8][9][10]. For these reasons, reductions in the rate or risk of PEx have been included within the bases of approval for several chronic CF respiratory therapies, including dornase alpha, inhaled tobramycin, and cystic fibrosis transmembrane conductance regulator (CFTR) modulators. ...
... That being said, it is difficult to parse the extent to which airway infection may be a cause and/or a consequence of underlying CF airway dysfunction, with some evidence supporting the latter. For instance, we "know" that chronic P. aeruginosa airway infection is associated with more aggressive CF disease progression [6] and increased mortality risk [9,39]. Yet, it has been challenging to quantify benefits with respect to either PEx rate or lung disease progression when the airway secretions of pwCF are converted to long-term P. aeruginosa negativity via aggressive antimicrobial treatment of initial infection [16,40]. ...
Cystic fibrosis (CF) pulmonary exacerbations (PEx) are clinical events that commonly result in increased treatment burden, decreased quality of life, and accelerated lung disease progression. CF PEx have historically been approached as though dealing with acute infections, and antibiotic treatments have been associated with improved outcomes. In this review, we discuss data supporting a causal role of CF airway infection in PEx as well studies that highlight our knowledge gaps in regard to PEx definitions, pathophysiology, and optimal treatment approaches. In the era of highly effective cystic fibrosis transmembrane conductance regulator modulator therapy, and the continually increasing health and longevity of persons with CF, a better understanding of PEx and further optimization of PEx antibiotic treatment approaches are needed.
... (16) In recent years, some authors have recommended antibiotic therapy for an acute decline in FEV 1 (a decline ≥ 10% in percent predicted FEV 1 at baseline), even in the absence of clinical signs and symptoms. (17,18) They argue that this approach is associated with a greater likelihood of recovering lung function and has long-term benefits. (17,18) Several international CF guidelines recommend routine FEV 1 measurements at all medical encounters, (19)(20)(21) but this practice is not universally adopted for several reasons. ...
... (17,18) They argue that this approach is associated with a greater likelihood of recovering lung function and has long-term benefits. (17,18) Several international CF guidelines recommend routine FEV 1 measurements at all medical encounters, (19)(20)(21) but this practice is not universally adopted for several reasons. In developing countries such as Brazil, there are centres with limited technical and financial resources, which limit the availability of pulmonary function tests. ...
Objective:
Pulmonary disease in cystic fibrosis (CF) is characterised by recurrent episodes of pulmonary exacerbations (PExs), with acute and long-term declines in lung function (FEV1). The study sought to determine whether routine spirometry increases the frequency of PEx diagnosis, resulting in benefits to long-term pulmonary function.
Methods:
CF patients in the 5- to 18-year age bracket were followed for 1 year, during which they underwent spirometry before every medical visit. The main variables were the frequency of PEx diagnosis and use of antibiotics; the use of spirometry as a criterion for PEx diagnosis (a decline ≥ 10% in baseline FEV1); and median percent predicted FEV1 over time. The data were compared with those for the previous 24-month period, when spirometry was performed electively every 6 months.
Results:
The study included 80 CF patients. PExs were diagnosed in 27.5% of the visits, with a mean frequency of 1.44 PExs per patient/year in 2014 vs. 0.88 PExs per patient/year in 2012 (p = 0.0001) and 1.15 PExs per patient/year in 2013 (p = 0.05). FEV1 was used as a diagnostic feature in 83.5% of PExs. In 21.9% of PExs, the decision to initiate antibiotics was solely based on an acute decline in FEV1. The median percent predicted FEV1 during the follow-up year was 85.7%, being 78.5% in 2013 and 76.8% in 2012 (p > 0.05). The median percent predicted FEV1 remained above 80% during the two years after the study.
Conclusions:
Routine spirometry is associated with higher rates of diagnosis and treatment of PExs, possibly impacting long-term pulmonary function.
... Pseudomonas aeruginosa (Pa) is the most common pathogen in bacterial lung infections by adulthood for people with CF (pwCF). Chronic endobronchial infection with Pa is associated with poor lung function, increased pulmonary exacerbations, and increased mortality (4)(5)(6)(7). ...
Despite great progress in the field, chronic Pseudomonas aeruginosa ( Pa ) infections remain a major cause of morbidity and mortality in patients with cystic fibrosis, necessitating treatment with inhaled antibiotics. Pf phage is a filamentous bacteriophage produced by Pa that has been reported to act as a structural element in Pa biofilms. Pf presence has been associated with resistance to antibiotics and poor outcomes in cystic fibrosis, though the underlying mechanisms are unclear. Here, we have investigated how Pf phages and sputum biopolymers impede antibiotic diffusion using human sputum samples and fluorescent recovery after photobleaching. We demonstrate that tobramycin interacts with Pf phages and sputum polymers through electrostatic interactions. We also developed a set of mathematical models to analyze the complex observations. Our analysis suggests that Pf phages in sputum reduce the diffusion of charged antibiotics due to a greater binding constant associated with organized liquid crystalline structures formed between Pf phages and sputum polymers. This study provides insights into antibiotic tolerance mechanisms in chronic Pa infections and may offer potential strategies for novel therapeutic approaches.
Teaser
Pf phages and sputum polymers reduce antibiotic diffusion via electrostatic interactions and liquid crystal formation.
... PwCF with untreated episodes of FEV 1 pp decline are less likely to return to baseline than those who receive treatment with antibiotics. [6][7][8][9] In particular, those with higher baseline FEV 1 pp have been shown to experience steeper rates of decline and are least likely to receive treatment for acute decline in lung function. 9 10 Despite the importance of recognising and treating clinically significant FEV 1 decline, there are very few published care pathways that have shown improvement in the rate of treating FEV 1 decline. ...
Introduction
Cystic fibrosis (CF) is a systemic autosomal recessive condition characterised by progressive lung disease. CF pulmonary exacerbations (PEx) are episodes of worsening respiratory status, and frequent PEx are a risk factor for accelerated lung function decline, yet many people with CF (PwCF) go untreated at the time of decline. The goal of this quality improvement (QI) initiative was to improve recognition, treatment and follow-up of PEx in PwCF.
Methods
Using the Model for Improvement, the Cystic Fibrosis Learning Network (CFLN) initiated a QI innovation laboratory (iLab) with a global aim to decrease the rate of lung function decline in PwCF. The iLab standardised definitions for signals of PEx using a threshold for decline in forced expiratory volume in one second (FEV 1 ) and/or changes in symptoms. The FEV 1 decline signal was termed FIES (FEV 1 -indicated exacerbation signal). Processes for screening and recognition of FIES and/or symptom changes, a treatment algorithm and follow-up in the presence of a signal were tested concurrently in multiple settings.
Specific aims
The specific aim is to increase the per cent of PwCF assessed for a PEx signal at ambulatory encounters and to increase the per cent of recommendations to follow-up within 6 weeks for PwCF experiencing a PEx signal.
Results
FIES recognition increased from 18.6% to 73.4% across all teams during the iLab, and every team showed an improvement. Of PwCF assessed, 15.8% experienced an FIES event (>10% decline in FEV 1 per cent predicted (FEV 1 pp)). Follow-up within 6 weeks was recommended for an average of 70.5% of those assessed for FIES and had an FEV 1 pp decline greater than 5%.
Conclusion
The CFLN iLab successfully defined and implemented a process to recognise and follow-up PEx signals. This process has the potential to be spread to the larger CF community. Further studies are needed to assess the impact of these processes on PwCF outcomes.
... The CF lung disease process is typically characterized by acute and prolonged drops in lung function. Attenuated decreases in lung function relative to patient-and/or center-level norms, clinically termed rapid decline, typically manifest during adolescence and early adulthood (Konstan et al., 2007;Vandenbranden et al., 2012). Early rapid decline tends to happen in individuals with below-average lung function, infections, poor/deteriorating nutrition, increased antibiotic use, and more frequent hospitalizations. ...
Background
Cystic fibrosis (CF) is a genetic disease but is greatly impacted by non-genetic (social/environmental and stochastic) influences. Some people with CF experience rapid decline, a precipitous drop in lung function relative to patient- and/or center-level norms. Those who experience rapid decline in early adulthood, compared to adolescence, typically exhibit less severe clinical disease but greater loss of lung function. The extent to which timing and degree of rapid decline are informed by social and environmental determinants of health (geomarkers) is unknown.
Methods
A longitudinal cohort study was performed (24,228 patients, aged 6–21 years) using the U.S. CF Foundation Patient Registry. Geomarkers at the ZIP Code Tabulation Area level measured air pollution/respiratory hazards, greenspace, crime, and socioeconomic deprivation. A composite score quantifying social-environmental adversity was created and used in covariate-adjusted functional principal component analysis, which was applied to cluster longitudinal lung function trajectories.
Results
Social-environmental phenotyping yielded three primary phenotypes that corresponded to early, middle, and late timing of peak decline in lung function over age. Geographic differences were related to distinct cultural and socioeconomic regions. Extent of peak decline, estimated as forced expiratory volume in 1 s of % predicted/year, ranged from 2.8 to 4.1 % predicted/year depending on social-environmental adversity. Middle decliners with increased social-environmental adversity experienced rapid decline 14.2 months earlier than their counterparts with lower social-environmental adversity, while timing was similar within other phenotypes. Early and middle decliners experienced mortality peaks during early adolescence and adulthood, respectively.
Conclusion
While early decliners had the most severe CF lung disease, middle and late decliners lost more lung function. Higher social-environmental adversity associated with increased risk of rapid decline and mortality during young adulthood among middle decliners. This sub-phenotype may benefit from enhanced lung-function monitoring and personalized secondary environmental health interventions to mitigate chemical and non-chemical stressors.
... Studies have shown that the decline in lung function occurs gradually and the annual rate of FEV 1 decline varies between 1.0 to 2.5% in children and adolescents. [19][20][21] This is in accordance with the annual rate of decline found in the present study (approximately 3%). In addition, present data showed a significant increase in the FEV 1 / FVC ratio and FEF 25-75% in the social distancing period, without a decrease in other parameters during this period. ...
Objective
To evaluate the impact of COVID-19 social distancing recommendations on nutritional status, pulmonary function, and morbidity in patients with cystic fibrosis (CF).
Methods
A retrospective cohort study including patients older than six years with a diagnosis of CF was performed. Demographic and clinical data, anthropometric measurements, pulmonary function, days of antibiotic use, and length of hospital stay were recorded. Variables were recorded at three time points relative to the baseline for implementation of social distancing measures: T-1 (14 months before implementation), T0 (baseline), and T1 (14 months after implementation). Delta (Δ) was calculated for each period: Δ1 (pre-pandemic T0-T-1) and Δ2 (pandemic T1-T0).
Results
The study included 25 patients, with a mean age of 11.7±4.3 years. The mean forced expiratory volume in the first second (FEV1) was 85.6±23.6%, and body mass index (BMI) was 17.5±3.0 kg/m². When comparing the two periods (Δ1 and Δ2), there was a significant increase in the FEV1/forced vital capacity (FVC) ratio (p=0.013) and in the forced expiratory flow between 25 and 75% of vital capacity (FEF25–75%) (p=0.037) in the pandemic period. There was also a significant reduction (p=0.005) in the use of antibiotics in the pandemic period compared with the pre-pandemic period. The Δ1 and Δ2 values did not differ significantly for BMI, FEV1, or length of hospital stay.
Conclusions
COVID-19 social distancing recommendations had a positive impact (decrease) on morbidity (use of antibiotics) and small airway obstruction (FEF25–75%) in patients with CF.
Keywords:
Cystic fibrosis; Social isolation; Pulmonary function; Nutritional status; Morbidity; SARS-CoV-2
... According to the US Cystic Fibrosis Foundation Patient Registry (CFFPR) Annual Report, the estimated prevalence of monthly, daily or weekly SHSe in individuals with CF aged < 18 years in the US is about 17% among those who report it; however, smoke exposure is unknown for 38.4% of people with CF who are followed in the registry [4] . Characterized by declining lung function and recurrent infections [5] , clinical evaluation and monitoring of CF lung disease progression requires regular pulmonary function testing particularly during adolescence and young adulthood when individuals are at highest risk of rapid lung function decline [6] . Despite differences in how SHSe data are collected (e.g.: selfreport as in the US CFFPR Registry [4] versus biomarker measurements like urine cotinine concentration [7] , the emphasis is largely on lung function, measured as forced expiratory volume in 1 second of % predicted (hereafter, FEV 1 % predicted), as the outcome. ...
Background:
Secondhand smoke exposure, an important environmental health factor in cystic fibrosis (CF), remains uniquely challenging to children with CF as they strive to maintain pulmonary function during early stages of growth and throughout adolescence. Despite various epidemiologic studies among CF populations, little has been done to coalesce estimates of the association between secondhand smoke exposure and lung function decline.
Methods:
A systematic review was performed using PRISMA guidelines. A Bayesian random-effects model was employed to estimate the association between secondhand smoke exposure and change in lung function (measured as FEV1% predicted).
Results:
Quantitative synthesis of study estimates indicated that second-hand smoke exposure corresponded to a significant drop in FEV1 (estimated decrease: -5.11% predicted; 95% CI: -7.20, -3.47). The estimate of between-study heterogeneity was 1.32% predicted (95% CI: 0.05, 4.26). There was moderate heterogeneity between the 6 analyzed studies that met review criteria (degree of heterogeneity: I2=61.9% [95% CI: 7.3-84.4%] and p = 0.022 from the frequentist method.) CONCLUSIONS: Our results quantify the impact at the pediatric population level and corroborate the assertion that secondhand smoke exposure negatively affects pulmonary function in children with CF. Findings highlight challenges and opportunities for future environmental health interventions in pediatric CF care.
... The mortality hazard is recalculated in each model cycle by adjusting for changes in these characteristics over time, and each individual is simulated until death [25]. The impact of ivacaftor treatment on survival is modeled indirectly via its impact on lung function in terms of acute change in ppFEV 1 , reduction in the rate of ppFEV 1 decline over time, and reduction in the number of PEx requiring treatment, as well as improvement in nutritional status in terms of weight-for-age z-score (Table 1) [10,13,14,35,[37][38][39][40]. While the model appeared to provide plausible estimates of the lifetime impact of ivacaftor, additional investigation was warranted to confirm the predictive validity of combining the Liou CPH equation with the reference survival curves to model the survival impact of both disease progression and ivacaftor treatment. ...
Objectives:
Cystic fibrosis (CF) is a rare genetic disease characterized by life-shortening lung function decline. Ivacaftor, a CF transmembrane conductance regulator modulator (CFTRm), was approved in 2012 for people with CF with specific gene mutations. We used real-world evidence of 5-year mortality impacts of ivacaftor in a US registry population to validate a CF disease-progression model that estimates the impact of ivacaftor on survival.
Methods:
The model projects the impact of ivacaftor vs. standard care in people with CF aged ≥6 years with CFTR gating mutations by combining parametric equations fitted to historical registry survival data, with mortality hazards adjusted for fixed and time-varying person-level characteristics. Disease progression with standard care was derived from published registry studies and the expected impact of ivacaftor on clinical characteristics was derived from clinical trials. Individual-level baseline characteristics of the registry ivacaftor-treated population were entered into the model; 5-year model-projected mortality with credible intervals (CrIs) was compared with registry mortality to evaluate the model's validity.
Results:
Post-calibration 5-year mortality projections closely approximated registry mortality in populations treated with standard care (6.4% modeled [95% CrI: 5.3% to 7.6%] vs. 6.0% observed) and ivacaftor (3.4% modeled [95% CrI: 2.7% to 4.4%] vs. 3.1% observed). The model accurately predicted 5-year relative risk of mortality (0.53 modeled [0.47 to 0.60] vs. 0.51 observed) in people treated with ivacaftor vs. standard care.
Conclusions:
Modeled 5-year survival projections for people with CF initiating ivacaftor vs. standard care align closely with real-world registry data. Findings support the validity of modeling CF to predict long-term survival and estimate clinical and economic outcomes of CFTRm.
... Many risk factors influence the progression of CF lung disease and early mortality (16), (17), but their relative impact over time has been uncertain. Previous studies have typically focused on a limited number of intrinsic (e.g., meconium ileus (18), genotype (19), (20)), or extrinsic (e.g., pulmonary exacerbations) (21) risk factors. ...
Aim
To examine the trajectory of forced expiratory volume in 1 s (FEV1) using data from the European Cystic Fibrosis (CF) Society Patient Registry collected from 2008 to 2016, hence the era before highly effective modulator therapy (HEMT). We evaluated risk factors for FEV1 decline.
Methods
The study population included patients with a confirmed diagnosis of CF recorded in the ECFPR (2008–2016). The evolution of FEV1% predicted with age (%FEV1), and the yearly change in %FEV1 were evaluated. Risk factors considered were CFTR mutation class, gender, age at diagnosis, neonatal screening, meconium ileus, sweat chloride concentration at diagnosis, and country's income level.
Results
We used 199,604 FEV1 recordings from 38,734 patients. The fastest decline was seen during puberty and in patients diagnosed before ten years. Males had a higher %FEV1 but a higher yearly %FEV1 loss between ages 15 and 25. We showed stabilization and even improvement in %FEV1 over age in adults with a class III mutation but a steady decline in patients homozygous for F508del or with both mutations of classes I/II. A faster decline in %FEV1 was found in patients from 'low-income' countries compared to a similar %FEV1 evolution in patients from middle- and high-income countries.
Conclusions
These longitudinal FEV1 data reflect the reality of CF across Europe in the era pre-HEMT and can serve as baseline for comparison with the post-HEMT era. The similar evolution in middle- and high-income countries underlines opportunities for low-income countries.
... A diverse group of other opportunistic bacteria, mycobacteria, and fungi may also be found in CF patients' respiratory areas [202]. The acquisition of certain pathogens, particularly P. aeruginosa and Burkholderia species, is associated with substantial clinical deterioration [203][204][205][206][207]. Increasingly, however, the culture-independent analysis of CF respiratory samples has identified that the microbial communities within the CF lung are much more complex than is suggested by standard culture alone. ...
The wide diversity of microbiota at the genera and species levels across sites and individuals is related to various causes and the observed differences between individuals. Efforts are underway to further understand and characterize the human-associated microbiota and its microbiome. Using 16S rDNA as a genetic marker for bacterial identification improved the detection and profiling of qualitative and quantitative changes within a bacterial population. In this light, this review provides a comprehensive overview of the basic concepts and clinical applications of the respiratory microbiome, alongside an in-depth explanation of the molecular targets and the potential relationship between the respiratory microbiome and respiratory disease pathogenesis. The paucity of robust evidence supporting the correlation between the respiratory microbiome and disease pathogenesis is currently the main challenge for not considering the microbiome as a novel druggable target for therapeutic intervention. Therefore, further studies are needed, especially prospective studies, to identify other drivers of microbiome diversity and to better understand the changes in the lung microbiome along with the potential association with disease and medications. Thus, finding a therapeutic target and unfolding its clinical significance would be crucial.
... Several studies have highlighted the contribution of demographic and clinical factors in the variability of respiratory disease. It has been shown that women and pwCF with poor nutritional status are at greater risk of severe disease [14,15]; pwCF with CF-related diabetes (CFRD) have a more rapid decline in respiratory function [16]; CF-liver disease (CFLD) increases susceptibility to infection [17]; and the age at chronic colonization with Pseudomonas aeruginosa (Pa) decreases in the most recent cohorts [18,19]. Nevertheless, many of these factors have been questioned and remain controversial [20,21]. ...
Although cystic fibrosis (CF) is recognized as a monogenic disease, due to variants within the CFTR (Cystic Fibrosis Transmembrane Regulator) gene, an extreme clinical heterogeneity is described among people with CF (pwCF). Apart from the exocrine pancreatic status, most studies agree that there is little association between CFTR variants and disease phenotypes. Environmental factors have been shown to contribute to this heterogeneity, accounting for almost 50% of the variability of the lung function of pwCF. Nevertheless, pwCF with similar CFTR variants and sharing the same environment (such as in siblings) may have highly variable clinical manifestations not explained by CFTR variants, and only partly explained by environmental factors. It is recognized that genetic variants located outside the CFTR locus, named “modifier genes”, influence the clinical expression of the disease. This short review discusses the latest studies that have described modifier factors associated with the various CF phenotypes as well as the response to the recent CFTR modulator therapies.
... Severe exacerbations have been associated with decreased lung function (5,6), CF-related diabetes (7), sleep disturbances (8), and reduced health-related quality of life (9). Severe pulmonary exacerbations have well-recognized long-term effects. ...
Background
Ivacaftor (IVA) improves lung function and other extrapulmonary outcomes in people with cystic fibrosis (CF). However, the effect of initiating IVA at earlier versus later ages has not been studied.
Methods
We conducted an observational cohort study of people in the US CF Foundation Patient Registry aged ≥6 years with ≥1 CF transmembrane conductance regulator–gating mutation to compare the effects of initiating IVA at earlier ages on per cent predicted forced expiratory volume in 1 s (ppFEV 1 ) and pulmonary exacerbation (PEx) outcomes. People with CF were grouped by age at IVA initiation (ages 6–10, 11–15, 16–20 and 21–25 years) to perform three analyses of younger versus older IVA initiation (6–10 vs 11–15, 11–15 vs 16–20 and 16–20 vs 21–25 years). For each analysis, baseline characteristics assessed over 1-year periods at the same age prior to IVA initiation were balanced by standardised mortality/morbidity ratio (SMR) weighting. For each analysis, outcomes were compared over a 5-year outcome assessment period when both groups were in the same age range and receiving IVA.
Findings
Baseline characteristics were well balanced between younger and older IVA initiator groups after SMR weighting. In the outcome assessment period, younger IVA initiators had significantly higher mean ppFEV 1 than older initiators across all comparisons, and those initiating IVA between ages 6–10 and 11–15 years had significantly lower PEx rates.
Interpretation
Study findings showed the importance of early IVA initiation in people with CF.
Rationale:
Pulmonary exacerbations (PEx) remain the most common cause of morbidity, recurrent hospitalization and diminished survival in people with CF (PWCF), and are characterized by excess inflammation. Corticosteroids are potent, widely available anti-inflammatory drugs. However, corticosteroid efficacy data from randomized controlled trials (RCTs) in PWCF are limited.
Objectives:
To determine whether adjunctive systemic corticosteroid therapy is associated with improved outcomes in acute CF PEx.
Methods:
We performed a secondary analysis of STOP2, a large multicenter RCT of antimicrobial treatment durations for adult PWCF presenting with PEx, that included the use of corticosteroids as a stratification criterion in its randomization protocol. Corticosteroid treatment effects were determined after propensity score-matching for covariates including age, sex, baseline FEV1, genotype and randomization arm. The primary outcome measure was the change in percent predicted FEV1 (ppFEV1). Symptoms, time to next PEx and the incidence of adverse events (AEs) and serious adverse events (SAEs) were assessed as secondary endpoints. Phenotypic factors associated with the clinical decision to prescribe steroids were also investigated.
Results:
Corticosteroids were prescribed for 168 of 982 PEx events in STOP2 (17%). Steroid prescription was associated with decreased baseline ppFEV1, increased age, and female sex. Co-treatment with corticosteroids was independent of treatment arm allocation, and did not result in greater mean ppFEV1 response, longer median time to next PEx or more substantial symptomatic improvement compared to propensity-matched PWCF receiving antibiotics alone. AEs were not increased in corticosteroid-treated PWCF. The total number of SAEs - but not the number of corticosteroid-related or PEx-ralated SAEs - was higher among patients receiving corticosteroids.
Conclusion:
Empiric, physician-directed treatment with systemic corticosteroids, while common, is not associated with improved clinical outcomes in PWCF receiving antibiotics for PEx.
Background
While bacteria identification on respiratory cultures is associated with poor short‐term outcomes in children with bronchopulmonary dysplasia (BPD) and tracheostomies, the influence on longer‐term respiratory support needs remains unknown.
Objective
To determine if respiratory culture growth of pathogenic organisms is associated with ongoing need for respiratory support, decannulation, and death at 3 years posttracheostomy placement in children with BPD and tracheostomies.
Methods
This single center, retrospective cohort study included infants and children with BPD and tracheostomies placed 2010–2018 and ≥1 respiratory culture obtained in 36 months posttracheostomy. Primary predictor was any pathogen identified on respiratory culture. Additional predictors were any Pseudomonas aeruginosa and chronic P. aeruginosa identification. Outcomes included continued use of respiratory support (e.g., oxygen, positive pressure), decannulation, and death at 3 years posttracheostomy. We used Poisson regression models to examine the relationship between respiratory organisms and outcomes, controlling for patient‐level covariates and within‐patient clustering.
Results
Among 170 children, 59.4% had a pathogen identified, 28.8% ever had P. aeruginosa , and 3.5% had chronic P. aeruginosa . At 3 years, 33.1% of alive children required ongoing respiratory support and 24.8% achieved decannulation; 18.9% were deceased. In adjusted analysis, any pathogen and P. aeruginosa were not associated with ongoing respiratory support or mortality. However, P. aeruginosa was associated with decreased decannulation probability (adjusted risk ratio 0.48, 95% CI 0.23–0.98). Chronic P. aeruginosa was associated with lower survival probability.
Conclusion
Our findings suggest that respiratory pathogens including P. aeruginosa may not promote long‐term respiratory dysfunction, but identification of P. aeruginosa may delay decannulation.
Purpose of review:
Pulmonary exacerbations are critical events with significant negative impacts in persons with cystic fibrosis, but their diagnosis and management are highly variable. Highly effective modulator therapies have greatly improved health and reduced exacerbation events, but have also reshaped how they present. This review discusses the complexities of the diagnosis and management of pulmonary exacerbations as well as the emerging work and evidence in this area.
Recent findings:
The shifting epidemiology and our understanding of risk factors for pulmonary exacerbations are discussed. As symptoms may be more subtle in the modulator context, novel technologies including studies of remote monitoring are presented. The continued relevance of pulmonary exacerbations, the heterogeneity in their management, as well as current and forthcoming clinical trials to optimize treatment approaches are detailed.
Summary:
In spite of the dramatic reductions in pulmonary exacerbations, airway infections persist, a proportion of persons with cystic fibrosis either on or off modulator therapies continue to experience exacerbation events, and long-term data is lacking. Innovative approaches and studies will be crucial to enable standardized and generalizable strategies to improve outcomes in persons with cystic fibrosis.
Background:
Handheld spirometry allows monitoring of lung function at home, of particular importance during the COVID-19 pandemic. Pediatric studies are unclear on whether values are interchangeable with traditional, clinic-based spirometry. We aimed to assess differences between contemporaneous, home (unsupervised) and clinic (supervised) spirometry and the variability of the former. The accuracy of the commercially available spirometer used in the study was also tested.
Methods:
Data from participants in the Clinical Monitoring and Biomarkers to stratify severity and predict outcomes in children with cystic fibrosisc (CLIMB-CF) Study aged ≥ 6 years who had paired (±1 day) clinic and home forced expiratory volume in 1 s (FEV1 ) readings were analyzed. Variability during clinical stability over 6-months was assessed. Four devices from Vitalograph were tested using 1 and 3 L calibration syringes.
Results:
Sixty-seven participants (median [interquartile range] age 10.7 [7.6-13.9] years) provided home and clinic FEV1 data pairs. The mean (SD) FEV1 % bias was 6.5% [±8.2%]) with wide limits of agreement (-9.6% to +22.7%); 76.2% of participants recorded lower results at home. Coefficient of variation of home FEV1 % during stable periods was 9.9%. Data from the testing of the handheld device used in CLIMB-CF showed a potential underread.
Conclusion:
In children and adolescents, home spirometry using hand-held equipment cannot be used interchangeably with clinic spirometry. Home spirometry is moderately variable during clinical stability. New handheld devices underread, particularly at lower volumes of potential clinical significance for smaller patients; this suggests that supervision does not account fully for the discrepancy. Opportunities should be taken to obtain dual device measurements in clinic, so that trend data from home can be utilized more accurately.
Newborn screening (NBS) for cystic fibrosis (CF) was fully implemented in the US by 2010, but delays in timeliness of evaluation for infants with positive NBS tests persist. Through evaluation of national patient registry data, we determined that late initiation of CF care is associated with poorer long-term nutritional outcomes.
Antibiotic resistance is a global public health threat. The care of chronic infections is complicated by bacterial biofilms. Biofilm embedded cells can be up to 1000-fold more tolerant to antibiotic treatment than planktonic cells. Antibiotic tolerance is a condition which does not involve mutation and enables bacteria to survive in the presence of antibiotics. The antibiotic tolerance of biofilm-cells often renders antibiotics ineffective, even against strains that do not carry resistance-impairing mutations. This review discusses bacterial iron homeostasis and the strategies being developed to target this bacterial vulnerability, with emphasis on a recently proposed approach which aims at targeting the iron storage protein bacterioferritin (Bfr) and its physiological partner, the ferredoxin Bfd. Bfr regulates cytosolic iron concentrations by oxidizing Fe2+ and storing Fe3+ in its internal cavity, and by forming a complex with Bfd to reduce Fe3+ in the internal cavity and release Fe2+ to the cytosol. Blocking the Bfr-Bfd complex in P. aeruginosa cells causes an irreversible accumulation of Fe3+ in BfrB and simultaneous cytosolic iron depletion, which leads to impaired biofilm maintenance and biofilm cell death. Recently discovered small molecule inhibitors of the Bfr-Bfd complex, which bind Bfr at the Bfd binding site, inhibit iron mobilization, and elicit biofilm cell death.
Background:
Introduction of novel therapies for cystic fibrosis (CF), raises the question whether traditional treatments can be withdrawn. Nebulized hypertonic saline (HS) could potentially be discontinued in patients receiving Dornase alfa (DA).
Research question:
In the pre-modulator era, did people with CF who were F508del homozygous (CFF508del) and received DA and HS have better preserved lung function than those treated with DA only?
Study design:
Retrospective analysis of CF Foundation Patient Registry data (2006-2014). Among 13,406 CFF508del with data for at least 2 consecutive years, 1,241 CFF508del had spirometry results and were treated with DA for 1-5 years without DA or HS during the preceding (baseline) year. Absolute percent predicted FEV1 (ppFEV1) change while on DA and HS relative to DA only was the main outcome. A marginal structural model was applied to assess the effect of 1-5 years of HS while controlling for time-dependent confounding.
Results:
Of 1,241 CFF508del, 619 (median baseline age 14.6 years; IQR 6-53) received DA only and 622 (14.55 years; IQR 6-48.1) were treated with DA and HS for 1-5 years. After 1 year, subjects receiving DA and HS had ppFEV1 that averaged 6.60% lower than ppFEV1 in those treated with DA only (95%CI: -8.54% to -4.66%; P<.001). Lower lung function in the former relative to the latter persisted throughout follow-up, highlighting confounding by indication. After accounting for baseline age, sex, race, DA use duration, baseline and previous year's ppFEV1 and time-varying clinical characteristics, DA and HS for 1-5 years were similar to DA only regarding ppFEV1 (year 1: mean ppFEV1 change +0.53% [95%CI: -0.66% to +1.71%; P=.38]; year 5: -1.82% [-4.01% to +0.36%; P=.10].
Interpretation:
In the pre-modulator era, CFF508del had no significant difference in lung function when nebulized HS was added to DA for 1-5 years.
Background:
Pseudomonas aeruginosa (Pa) infection in cystic fibrosis (CF) is characterized in stages: never (prior to first positive culture) to incident (first positive culture) to chronic. The association of Pa infection stage with lung function trajectory is poorly understood and the impact of age on this association has not been examined. We hypothesized that FEV1 decline would be slowest prior to Pa infection, intermediate after incident infection and greatest after chronic Pa infection.
Methods:
Participants in a large US prospective cohort study diagnosed with CF prior to age 3 contributed data through the U.S. CF Patient Registry. Cubic spline linear mixed effects models were used to evaluate the longitudinal association of Pa stage (never, incident, chronic using 4 different definitions) with FEV1 adjusted for relevant covariates. Models contained interaction terms between age and Pa stage.
Results:
1,264 subjects born 1992-2006 provided a median 9.5 (IQR 0.25 to 15.75) years of follow up through 2017. 89% developed incident Pa; 39-58% developed chronic Pa depending on the definition. Compared to never Pa, incident Pa infection was associated with greater annual FEV1 decline and chronic Pa infection with the greatest FEV1 decline. The most rapid FEV1 decline and strongest association with Pa infection stage was seen in early adolescence (ages 12-15).
Conclusions:
Annual FEV1 decline worsens significantly with each Pa infection stage in children with CF. Our findings suggest that measures to prevent chronic infection, particularly during the high-risk period of early adolescence, could mitigate FEV1 decline and improve survival.
Rationale:
Cystic Fibrosis (CF) is a genetic disease leading to progressive lung function loss and early mortality. Many clinical and demographic variables are associated with lung function decline, but little is known about the effects of prolonged periods of missed care.
Objectives:
To determine if missed care in the US Cystic Fibrosis Foundation Patient Registry (CFFPR) is associated with decreased lung function at follow-up visits.
Methods:
De-identified US Cystic Fibrosis Foundation Patient Registry (CFFPR) data for 2004-2016 was analyzed, with the exposure of interest being ≥ 12-month gap in CF registry data. We modeled percent predicted forced expiratory volume in one second (FEV1PP) using longitudinal semiparametric modeling with natural cubic splines for age (knots at quantiles) and with subject-specific random effects, adjusted for gender and cystic fibrosis transmembrane conductance regulator (CFTR) genotype, race, and ethnicity and included time-varying covariates for gaps in care, insurance type, underweight BMI, CF-related diabetes status, and chronic infections.
Results:
24,328 individuals with 1,082,899 encounters in the CFFPR met inclusion criteria. 8,413 (35%) individuals in the cohort had at least a single ≥ 12-month episode of discontinuity, whereas 15,915 (65%) had continuous care. 75.8% of all encounters preceded by a 12-month gap occurred in patients 18 years or older. Compared to those with continuous care, those with a discontinuous care episode had a lower follow-up FEV1PP at the index visit (-0.81%; 95% CI -1.00, -0.61), after adjustment for other variables. The magnitude of this difference was much greater (-2.1%; 95% CI -1.5, -2.7) in young adult F508del homozygotes.
Conclusions:
There was a high rate of ≥ 12-month gap in care, especially in adults, documented in the CFFPR. Discontinuous care identified in the US CFFPR was strongly associated with decreased lung function, especially in adolescents and young adults homozygous for the F508del CFTR mutation. This may have implications for identifying and treating people with lengthy gaps in care and have implications for CFF care recommendations.
Rationale:
Studies estimating rate of lung function decline in cystic fibrosis (CF) have been inconsistent regarding methods used. How the methodology used impacts validity of the results and comparability between studies is unknown.
Objectives:
The Cystic Fibrosis Foundation established a workgroup whose tasks were to examine the impact of differing approaches to estimating rate of decline in lung function and to provide analysis guidelines.
Methods:
We utilized a natural history cohort of 35,252 individuals with CF aged > 6 years of the Cystic Fibrosis Foundation Patient Registry (CFFPR), 2003-2016. Modeling strategies using linear and nonlinear forms of marginal and mixed-effects models, which have previously quantified rate of forced expiratory volume in 1 second (FEV1) decline (% predicted/year), were evaluated under clinically relevant scenarios of available lung function data. Scenarios varied by sample size (overall CFFPR, medium-sized cohort of 3,000 subjects, and small-sized cohort of 150), data collection/reporting frequency (encounter, quarterly, and annual), inclusion of FEV1 during pulmonary exacerbation, and follow-up length (<2 years, 2-5 years, entire duration).
Results:
Rate-of-FEV1-decline estimates (% predicted/year) differed between linear marginal and mixed-effects models; overall cohort estimates (95% confidence interval) were 1.26 (1.24-1.29) and 1.40 (1.38-1.42), respectively. Marginal models consistently estimated less rapid lung function decline than mixed-effects models across scenarios except for short-term follow-up (both were ~1.4). Rate-of-decline estimates from nonlinear models diverged by age 30. Among mixed-effects models, nonlinear and stochastic terms fit best except for short-term follow-up (< 2 years). Overall CFFPR analysis from a joint longitudinal-survival model implied that an increase in rate of decline of 1% predicted/year in FEV1 associated with a 1.52-fold (52%) increase in the hazard of death/lung transplantation, but results exhibited immortal cohort bias.
Conclusions:
Differences were as high as 0.5% predicted/year between rate-of-decline estimates, but we found estimates were robust to lung function data availability scenarios except short-term follow-up and older age ranges. Inconsistencies among previous study results may be attributable to inherent differences in study design, inclusion criteria, or covariate adjustment. Results-based decision points reported herein will support researchers in selecting a strategy to model lung function decline most reflective of nuanced, study-specific goals.
Background:
Higher growth percentiles are associated with more favorable lung function in cystic fibrosis (CF), prompting the creation of CF Foundation (CFF) nutritional guidelines.
Objectives:
To describe early childhood growth trajectories within CF, to determine if growth trajectories are associated with differences in lung function at age six, and to identify factors that differ between trajectory groups.
Methods:
Retrospective cohort study of children diagnosed with CF and born 2000-2011 using the US CFF Patient Registry. Annualized growth parameters prior to age six were included in group-based trajectory modeling to identify unique early life growth trajectories. FEV1 percent predicted (FEV1pp) at age six was compared between trajectory groups using linear regression. Factors associated with group membership were identified using multinomial logistic regression.
Results:
6,809 children met inclusion criteria. Six discrete growth trajectories were identified, including three groups that began with growth parameters >50th percentile, termed: "always high", "gradual decliner", "rapid decliner", and three which began with growth parameters <50th percentile, termed: "rapid riser", "gradual riser", "always low". FEV1pp at age six was highest for the Always High trajectory. The Always Low trajectory was nearly 10% lower than the Always High trajectory. Sex, ethnicity, newborn screening and pancreatic function were associated with trajectory class membership.
Conclusions:
Distinct early life growth trajectories were identified within CF. Trajectories that met CFF nutritional guideline recommendations were associated with higher FEV1pp at age six. CF care teams should continue to partner with families to encourage interventions to support optimal growth to improve lung function in CF.
With the improving survival of cystic fibrosis (CF) patients and the advent of highly effective cystic fibrosis transmembrane conductance regulator (CFTR) therapy, the clinical spectrum of this complex multisystem disease continues to evolve. One of the most important clinical events for patients with CF in the course of this disease is acute pulmonary exacerbation (PEx). Clinical and microbial epidemiology studies of CF PEx continue to provide important insight into the disease course, prognosis, and complications. This work has now led to several large-scale clinical trials designed to clarify the treatment paradigm for CF PEx. The primary goal of this review is to provide a summary and update of the pathophysiology, clinical and microbial epidemiology, outcome and treatment of CF PEx, biomarkers for exacerbation, and the impact of highly effective modulator therapy on these events moving forward.
Progressive obstructive lung disease secondary to chronic airway infection, coupled with impaired host immunity, is the leading cause of morbidity and mortality in cystic fibrosis (CF). Classical pathogens found in the airways of persons with CF (pwCF) include Pseudomonas aeruginosa, Staphylococcus aureus, the Burkholderia cepacia complex, Achromobacter species, and Haemophilus influenzae. While traditional respiratory-tract surveillance culturing has focused on this limited range of pathogens, the use of both comprehensive culture and culture-independent molecular approaches have demonstrated complex highly personalized microbial communities. Loss of bacterial community diversity and richness, counteracted with relative increases in dominant taxa by traditional CF pathogens such as Burkholderia or Pseudomonas, have long been considered the hallmark of disease progression. Acquisition of these classic pathogens is viewed as a harbinger of advanced disease and postulated to be driven in part by recurrent and frequent antibiotic exposure driven by frequent acute pulmonary exacerbations. Recently, CF transmembrane conductance regulator (CFTR) modulators, small molecules designed to potentiate or restore diminished protein levels/function, have been successfully developed and have profoundly influenced disease course. Despite the multitude of clinical benefits, structural lung damage and consequent chronic airway infection persist in pwCF. In this article, we review the microbial epidemiology of pwCF, focus on our evolving understanding of these infections in the era of modulators, and identify future challenges in infection surveillance and clinical management.
Numerous studies indicate that outcomes for pediatric patients are improved when the anesthesia caregiver has advanced training and knowledge of pediatric anesthesiology. Essentials of Pediatric Anesthesiology is a unique new handbook, providing a clinically relevant and easy-to-read review of all key topics in this important field. Written and edited by leading pediatric anesthesia physicians, each chapter takes a consistent approach, guaranteeing this book is user-friendly and authoritative throughout. Topics include physiology, anatomy, equipment, a comprehensive overview of relevant disease states, and special topics such as regional anesthesia, complications, and anesthesia for remote locations. Numerous diagrams, tables and figures help to organize the information for easy reference. Whether you choose to dip into a particular chapter or read the book cover to cover, Essentials of Pediatric Anesthesiology is a valuable review book for all residents, fellows and clinical practitioners needing to improve or refresh their understanding of pediatric anesthesia management.
Numerous studies indicate that outcomes for pediatric patients are improved when the anesthesia caregiver has advanced training and knowledge of pediatric anesthesiology. Essentials of Pediatric Anesthesiology is a unique new handbook, providing a clinically relevant and easy-to-read review of all key topics in this important field. Written and edited by leading pediatric anesthesia physicians, each chapter takes a consistent approach, guaranteeing this book is user-friendly and authoritative throughout. Topics include physiology, anatomy, equipment, a comprehensive overview of relevant disease states, and special topics such as regional anesthesia, complications, and anesthesia for remote locations. Numerous diagrams, tables and figures help to organize the information for easy reference. Whether you choose to dip into a particular chapter or read the book cover to cover, Essentials of Pediatric Anesthesiology is a valuable review book for all residents, fellows and clinical practitioners needing to improve or refresh their understanding of pediatric anesthesia management.
Numerous studies indicate that outcomes for pediatric patients are improved when the anesthesia caregiver has advanced training and knowledge of pediatric anesthesiology. Essentials of Pediatric Anesthesiology is a unique new handbook, providing a clinically relevant and easy-to-read review of all key topics in this important field. Written and edited by leading pediatric anesthesia physicians, each chapter takes a consistent approach, guaranteeing this book is user-friendly and authoritative throughout. Topics include physiology, anatomy, equipment, a comprehensive overview of relevant disease states, and special topics such as regional anesthesia, complications, and anesthesia for remote locations. Numerous diagrams, tables and figures help to organize the information for easy reference. Whether you choose to dip into a particular chapter or read the book cover to cover, Essentials of Pediatric Anesthesiology is a valuable review book for all residents, fellows and clinical practitioners needing to improve or refresh their understanding of pediatric anesthesia management.
Numerous studies indicate that outcomes for pediatric patients are improved when the anesthesia caregiver has advanced training and knowledge of pediatric anesthesiology. Essentials of Pediatric Anesthesiology is a unique new handbook, providing a clinically relevant and easy-to-read review of all key topics in this important field. Written and edited by leading pediatric anesthesia physicians, each chapter takes a consistent approach, guaranteeing this book is user-friendly and authoritative throughout. Topics include physiology, anatomy, equipment, a comprehensive overview of relevant disease states, and special topics such as regional anesthesia, complications, and anesthesia for remote locations. Numerous diagrams, tables and figures help to organize the information for easy reference. Whether you choose to dip into a particular chapter or read the book cover to cover, Essentials of Pediatric Anesthesiology is a valuable review book for all residents, fellows and clinical practitioners needing to improve or refresh their understanding of pediatric anesthesia management.
Numerous studies indicate that outcomes for pediatric patients are improved when the anesthesia caregiver has advanced training and knowledge of pediatric anesthesiology. Essentials of Pediatric Anesthesiology is a unique new handbook, providing a clinically relevant and easy-to-read review of all key topics in this important field. Written and edited by leading pediatric anesthesia physicians, each chapter takes a consistent approach, guaranteeing this book is user-friendly and authoritative throughout. Topics include physiology, anatomy, equipment, a comprehensive overview of relevant disease states, and special topics such as regional anesthesia, complications, and anesthesia for remote locations. Numerous diagrams, tables and figures help to organize the information for easy reference. Whether you choose to dip into a particular chapter or read the book cover to cover, Essentials of Pediatric Anesthesiology is a valuable review book for all residents, fellows and clinical practitioners needing to improve or refresh their understanding of pediatric anesthesia management.
Numerous studies indicate that outcomes for pediatric patients are improved when the anesthesia caregiver has advanced training and knowledge of pediatric anesthesiology. Essentials of Pediatric Anesthesiology is a unique new handbook, providing a clinically relevant and easy-to-read review of all key topics in this important field. Written and edited by leading pediatric anesthesia physicians, each chapter takes a consistent approach, guaranteeing this book is user-friendly and authoritative throughout. Topics include physiology, anatomy, equipment, a comprehensive overview of relevant disease states, and special topics such as regional anesthesia, complications, and anesthesia for remote locations. Numerous diagrams, tables and figures help to organize the information for easy reference. Whether you choose to dip into a particular chapter or read the book cover to cover, Essentials of Pediatric Anesthesiology is a valuable review book for all residents, fellows and clinical practitioners needing to improve or refresh their understanding of pediatric anesthesia management.
Numerous studies indicate that outcomes for pediatric patients are improved when the anesthesia caregiver has advanced training and knowledge of pediatric anesthesiology. Essentials of Pediatric Anesthesiology is a unique new handbook, providing a clinically relevant and easy-to-read review of all key topics in this important field. Written and edited by leading pediatric anesthesia physicians, each chapter takes a consistent approach, guaranteeing this book is user-friendly and authoritative throughout. Topics include physiology, anatomy, equipment, a comprehensive overview of relevant disease states, and special topics such as regional anesthesia, complications, and anesthesia for remote locations. Numerous diagrams, tables and figures help to organize the information for easy reference. Whether you choose to dip into a particular chapter or read the book cover to cover, Essentials of Pediatric Anesthesiology is a valuable review book for all residents, fellows and clinical practitioners needing to improve or refresh their understanding of pediatric anesthesia management.
Numerous studies indicate that outcomes for pediatric patients are improved when the anesthesia caregiver has advanced training and knowledge of pediatric anesthesiology. Essentials of Pediatric Anesthesiology is a unique new handbook, providing a clinically relevant and easy-to-read review of all key topics in this important field. Written and edited by leading pediatric anesthesia physicians, each chapter takes a consistent approach, guaranteeing this book is user-friendly and authoritative throughout. Topics include physiology, anatomy, equipment, a comprehensive overview of relevant disease states, and special topics such as regional anesthesia, complications, and anesthesia for remote locations. Numerous diagrams, tables and figures help to organize the information for easy reference. Whether you choose to dip into a particular chapter or read the book cover to cover, Essentials of Pediatric Anesthesiology is a valuable review book for all residents, fellows and clinical practitioners needing to improve or refresh their understanding of pediatric anesthesia management.
Numerous studies indicate that outcomes for pediatric patients are improved when the anesthesia caregiver has advanced training and knowledge of pediatric anesthesiology. Essentials of Pediatric Anesthesiology is a unique new handbook, providing a clinically relevant and easy-to-read review of all key topics in this important field. Written and edited by leading pediatric anesthesia physicians, each chapter takes a consistent approach, guaranteeing this book is user-friendly and authoritative throughout. Topics include physiology, anatomy, equipment, a comprehensive overview of relevant disease states, and special topics such as regional anesthesia, complications, and anesthesia for remote locations. Numerous diagrams, tables and figures help to organize the information for easy reference. Whether you choose to dip into a particular chapter or read the book cover to cover, Essentials of Pediatric Anesthesiology is a valuable review book for all residents, fellows and clinical practitioners needing to improve or refresh their understanding of pediatric anesthesia management.
Numerous studies indicate that outcomes for pediatric patients are improved when the anesthesia caregiver has advanced training and knowledge of pediatric anesthesiology. Essentials of Pediatric Anesthesiology is a unique new handbook, providing a clinically relevant and easy-to-read review of all key topics in this important field. Written and edited by leading pediatric anesthesia physicians, each chapter takes a consistent approach, guaranteeing this book is user-friendly and authoritative throughout. Topics include physiology, anatomy, equipment, a comprehensive overview of relevant disease states, and special topics such as regional anesthesia, complications, and anesthesia for remote locations. Numerous diagrams, tables and figures help to organize the information for easy reference. Whether you choose to dip into a particular chapter or read the book cover to cover, Essentials of Pediatric Anesthesiology is a valuable review book for all residents, fellows and clinical practitioners needing to improve or refresh their understanding of pediatric anesthesia management.
Numerous studies indicate that outcomes for pediatric patients are improved when the anesthesia caregiver has advanced training and knowledge of pediatric anesthesiology. Essentials of Pediatric Anesthesiology is a unique new handbook, providing a clinically relevant and easy-to-read review of all key topics in this important field. Written and edited by leading pediatric anesthesia physicians, each chapter takes a consistent approach, guaranteeing this book is user-friendly and authoritative throughout. Topics include physiology, anatomy, equipment, a comprehensive overview of relevant disease states, and special topics such as regional anesthesia, complications, and anesthesia for remote locations. Numerous diagrams, tables and figures help to organize the information for easy reference. Whether you choose to dip into a particular chapter or read the book cover to cover, Essentials of Pediatric Anesthesiology is a valuable review book for all residents, fellows and clinical practitioners needing to improve or refresh their understanding of pediatric anesthesia management.
Numerous studies indicate that outcomes for pediatric patients are improved when the anesthesia caregiver has advanced training and knowledge of pediatric anesthesiology. Essentials of Pediatric Anesthesiology is a unique new handbook, providing a clinically relevant and easy-to-read review of all key topics in this important field. Written and edited by leading pediatric anesthesia physicians, each chapter takes a consistent approach, guaranteeing this book is user-friendly and authoritative throughout. Topics include physiology, anatomy, equipment, a comprehensive overview of relevant disease states, and special topics such as regional anesthesia, complications, and anesthesia for remote locations. Numerous diagrams, tables and figures help to organize the information for easy reference. Whether you choose to dip into a particular chapter or read the book cover to cover, Essentials of Pediatric Anesthesiology is a valuable review book for all residents, fellows and clinical practitioners needing to improve or refresh their understanding of pediatric anesthesia management.
Numerous studies indicate that outcomes for pediatric patients are improved when the anesthesia caregiver has advanced training and knowledge of pediatric anesthesiology. Essentials of Pediatric Anesthesiology is a unique new handbook, providing a clinically relevant and easy-to-read review of all key topics in this important field. Written and edited by leading pediatric anesthesia physicians, each chapter takes a consistent approach, guaranteeing this book is user-friendly and authoritative throughout. Topics include physiology, anatomy, equipment, a comprehensive overview of relevant disease states, and special topics such as regional anesthesia, complications, and anesthesia for remote locations. Numerous diagrams, tables and figures help to organize the information for easy reference. Whether you choose to dip into a particular chapter or read the book cover to cover, Essentials of Pediatric Anesthesiology is a valuable review book for all residents, fellows and clinical practitioners needing to improve or refresh their understanding of pediatric anesthesia management.
Numerous studies indicate that outcomes for pediatric patients are improved when the anesthesia caregiver has advanced training and knowledge of pediatric anesthesiology. Essentials of Pediatric Anesthesiology is a unique new handbook, providing a clinically relevant and easy-to-read review of all key topics in this important field. Written and edited by leading pediatric anesthesia physicians, each chapter takes a consistent approach, guaranteeing this book is user-friendly and authoritative throughout. Topics include physiology, anatomy, equipment, a comprehensive overview of relevant disease states, and special topics such as regional anesthesia, complications, and anesthesia for remote locations. Numerous diagrams, tables and figures help to organize the information for easy reference. Whether you choose to dip into a particular chapter or read the book cover to cover, Essentials of Pediatric Anesthesiology is a valuable review book for all residents, fellows and clinical practitioners needing to improve or refresh their understanding of pediatric anesthesia management.
Numerous studies indicate that outcomes for pediatric patients are improved when the anesthesia caregiver has advanced training and knowledge of pediatric anesthesiology. Essentials of Pediatric Anesthesiology is a unique new handbook, providing a clinically relevant and easy-to-read review of all key topics in this important field. Written and edited by leading pediatric anesthesia physicians, each chapter takes a consistent approach, guaranteeing this book is user-friendly and authoritative throughout. Topics include physiology, anatomy, equipment, a comprehensive overview of relevant disease states, and special topics such as regional anesthesia, complications, and anesthesia for remote locations. Numerous diagrams, tables and figures help to organize the information for easy reference. Whether you choose to dip into a particular chapter or read the book cover to cover, Essentials of Pediatric Anesthesiology is a valuable review book for all residents, fellows and clinical practitioners needing to improve or refresh their understanding of pediatric anesthesia management.
Numerous studies indicate that outcomes for pediatric patients are improved when the anesthesia caregiver has advanced training and knowledge of pediatric anesthesiology. Essentials of Pediatric Anesthesiology is a unique new handbook, providing a clinically relevant and easy-to-read review of all key topics in this important field. Written and edited by leading pediatric anesthesia physicians, each chapter takes a consistent approach, guaranteeing this book is user-friendly and authoritative throughout. Topics include physiology, anatomy, equipment, a comprehensive overview of relevant disease states, and special topics such as regional anesthesia, complications, and anesthesia for remote locations. Numerous diagrams, tables and figures help to organize the information for easy reference. Whether you choose to dip into a particular chapter or read the book cover to cover, Essentials of Pediatric Anesthesiology is a valuable review book for all residents, fellows and clinical practitioners needing to improve or refresh their understanding of pediatric anesthesia management.
Numerous studies indicate that outcomes for pediatric patients are improved when the anesthesia caregiver has advanced training and knowledge of pediatric anesthesiology. Essentials of Pediatric Anesthesiology is a unique new handbook, providing a clinically relevant and easy-to-read review of all key topics in this important field. Written and edited by leading pediatric anesthesia physicians, each chapter takes a consistent approach, guaranteeing this book is user-friendly and authoritative throughout. Topics include physiology, anatomy, equipment, a comprehensive overview of relevant disease states, and special topics such as regional anesthesia, complications, and anesthesia for remote locations. Numerous diagrams, tables and figures help to organize the information for easy reference. Whether you choose to dip into a particular chapter or read the book cover to cover, Essentials of Pediatric Anesthesiology is a valuable review book for all residents, fellows and clinical practitioners needing to improve or refresh their understanding of pediatric anesthesia management.
Numerous studies indicate that outcomes for pediatric patients are improved when the anesthesia caregiver has advanced training and knowledge of pediatric anesthesiology. Essentials of Pediatric Anesthesiology is a unique new handbook, providing a clinically relevant and easy-to-read review of all key topics in this important field. Written and edited by leading pediatric anesthesia physicians, each chapter takes a consistent approach, guaranteeing this book is user-friendly and authoritative throughout. Topics include physiology, anatomy, equipment, a comprehensive overview of relevant disease states, and special topics such as regional anesthesia, complications, and anesthesia for remote locations. Numerous diagrams, tables and figures help to organize the information for easy reference. Whether you choose to dip into a particular chapter or read the book cover to cover, Essentials of Pediatric Anesthesiology is a valuable review book for all residents, fellows and clinical practitioners needing to improve or refresh their understanding of pediatric anesthesia management.
Background:
Pulmonary Exacerbations (PEx), pathogens colonizing the respiratory tract, and patients' age are associated with progressive worsening of lung function among patients with Cystic Fibrosis (CF). However, the effect of these factors on longitudinal changes of LCI remains unclear.
Aim:
To assess the role of age, different types of bronchial infection, and PEx on LCI deterioration.
Methods:
We conducted a retrospective study assessing MBW and spirometry changes among CF patients evaluated at quarterly outpatient clinic visits over eight years. MBW and spirometry were performed at each visit, sputum samples and/or cough swabs were obtained for culture, whereas respiratory symptoms and clinical examination findings were recorded. Patients who had ≥5 serial MBW measurements, one of which coincided with a pulmonary exacerbation, were reviewed.
Results:
76 patients were included in the study: mean age 10.61 years (range 1.75 to 23.75). A total of 1152 MBW tests and 1047 spirometry tests were performed. LCI was significantly higher among CF patients aged 11 to 15, 16 to 20, and over 20 years than those under five years of age; ΔLCI: 1.16 (CI 0.43 to 1.90) and 3. 25 (CI 2.33 to 4.17), respectively. Furthermore, LCI was significantly elevated in CF patients with positive cultures for PsA (0.52 LCI (CI -0.12 to 0.71) and Stenotrophomonas Maltophilia (1.41 LCI (CI 0.61 to 2.21). Moreover, increased values of LCI in CF patients were significantly associated with increased risk of PEx (OR 1.19, CI [1.14 to 1.25], p <0.001).
Conclusion:
LCI demonstrates a progression of lung disease and corresponds to changes in bacterial infections and PEx among patients with CF. LCI may be a valuable marker for tracking disease deterioration and may have a role in the routine clinical care of patients with CF. This article is protected by copyright. All rights reserved.
Objectives:
Cost-effectiveness analysis (CEA) is useful to assess the value of health care interventions based on clinical effectiveness and costs. However, standard CEA methods make important assumptions that may significantly increase the incremental cost-effectiveness ratio (ICER) for lifelong treatments for rare, chronic diseases. We used the cost-effectiveness of elexacaftor/tezacaftor/ivacaftor and ivacaftor (ELX/TEZ/IVA) for the treatment of cystic fibrosis as a case study to explore how alternative assumptions for (1) discounting, (2) utility measures, (3) disease management costs, and (4) static drug pricing impact cost-effectiveness outcomes.
Materials and methods:
Cost-effectiveness of ELX/TEZ/IVA was evaluated using base-case inputs and assumptions reflecting standard CEA methods and was then compared with cost-effectiveness estimates obtained with alternate assumptions: (1) applying a lower discount rate to health benefits (1.5%) than costs (3%); (2) including a treatment-specific utility increment; (3) excluding disease management costs incurred during the period of extended survival attributable to ELX/TEZ/IVA treatment; and (4) decreasing the price of ELX/TEZ/IVA following loss of exclusivity.
Results:
Modifying assumptions for these four factors together reduced the ICER by 75% from the base case, with the largest reduction (45%) occurring when the price trajectory was modified to allow for generic entry. Differential discounting, use of a treatment-specific utility increment, and exclusion of additional disease management costs each individually reduced the ICER by 36%, 14%, and 10%, respectively, from the base case.
Conclusions:
This study illustrates the impact that modifications to standard CEA methods may have on measures of cost-effectiveness for rare, chronic diseases.
Since the inflammatory response to chronic infection contributes to lung destruction in patients with cystic fibrosis, we hypothesized that anti-inflammatory therapy might slow the progression of lung disease.
In a double-blind trial, 85 patients, 5 to 39 years of age, with mild lung disease (forced expiratory volume in one second [FEV1], > or = 60 percent of the predicted value) were randomly assigned to receive ibuprofen or placebo orally twice daily for four years. Doses were adjusted individually to achieve peak plasma concentrations of 50 to 100 micrograms per milliliter. Changes in pulmonary function, the percentage of ideal body weight, the chest-radiograph score, and the frequency of hospitalization were assessed.
Patients randomly assigned to ibuprofen had a slower annual rate of change in FEV1 than the patients assigned to placebo (mean [+/- SE] slope, -2.17 +/- 0.57 percent vs. -3.60 +/- 0.55 percent in the placebo group; P = 0.02), and weight (as a percentage of ideal body weight) was better maintained in the former group (P = 0.02). Among the patients who took ibuprofen for four years and had at least a 70 percent rate of compliance, the annual rate of change in FEV1 was even slower (-1.48 +/- 0.69 percent vs. -3.57 +/- 0.65 percent in the placebo group, P = 0.03), and this group of patients also had a significantly slower rate of decline in forced vital capacity, the percentage of ideal body weight, and the chest-radiograph score. There was no significant difference between the ibuprofen and placebo groups in the frequency of hospitalization. One patient was withdrawn from the study because of conjunctivitis, and one because of epistaxis related to ibuprofen.
In patients with cystic fibrosis and mild lung disease, high-dose ibuprofen, taken consistently for four years, significantly slows the progression of the lung disease without serious adverse effects.
A study was undertaken to evaluate whether an early diagnosis by neonatal screening may improve the long term prognosis of patients with cystic fibrosis and to assess the influence of expert management started immediately after the diagnosis.
Comparative clinical follow up in three birth cohorts of patients with cystic fibrosis was performed at the Cystic Fibrosis centre in Groningen in close collaboration with paediatricians in general hospitals in the north-eastern part of the Netherlands. The first birth cohort (n = 19) was detected by screening and the two other cohorts were detected clinically, one (n = 30) consisting of patients born during the screening programme and the other (n = 32) of patients born during the six years immediately after the screening programme ended. The total number of patients in the three birth cohorts included all patients with cystic fibrosis born in this area during a 12 year period. Cumulative survival rates and the variation with time of lung function, the levels of immunoglobulins, and growth patterns were used as main outcome measures.
Patients born during the screening programme but detected clinically appeared to have a reduced life expectancy compared with patients detected by screening. The patients detected by screening showed less deterioration in lung function (annual decrease 1.2% of FEV1 % pred), a smaller increase in immunoglobulin levels, and minimal catch-up growth compared with an annual decrease of 3.25% of FEV1 % pred in the non-screened birth cohort of the same age, a higher rise in immunoglobulins leading to increased levels at the end of the observation period, and catch-up growth for weight as well as height. Differences between patients treated in a cystic fibrosis centre and those not referred to a specialist centre were smaller but similar, in favour of treatment at a cystic fibrosis clinic.
Expert management started immediately after an early diagnosis of cystic fibrosis by neonatal screening results in important beneficial effects on the outcome and clinical course of the condition. The institution of very early treatment may be critical for the outcome and long term prognosis for most patients with cystic fibrosis. Neonatal screening programmes for cystic fibrosis should be introduced more widely.
The severity of lung disease in cystic fibrosis (CF) may be related to the type of mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, and to environmental and immunological factors. Since pulmonary disease is the main determinant of morbidity and mortality in CF, it is important to identify factors that can explain and predict this variation. The aim of this longitudinal study of the whole Swedish CF population over age 7 years was to correlate genetic and clinical data with the rate of decline in pulmonary function. The statistical analysis was performed using the mixed model regression method, supplemented with calculation of relative risks for severe lung disease in age cohorts.
The severity of pulmonary disease was to some extent predicted by CFTR genotype. Furthermore, the present investigation is the first long-term study showing a significantly more rapid deterioration of lung function in patients with concomitant diabetes mellitus. Besides diabetes mellitus, pancreatic insufficiency and chronic Pseudomonas colonization were found to be negative predictors of pulmonary function. In contrast to several other reports, we found no significant differences in lung function between genders. Patients with pancreatic sufficiency have no or only a slight decline of lung function with age once treatment is started, but an early diagnosis in this group is desirable. Pediatr Pulmonol. 2002; 33:483–491.
The German cystic fibrosis (CF) quality assurance (CFQA) project is a patient registry for CF which was founded in 1995. Relevant clinical and laboratory data, respiratory function test results, complications, and CF treatments are entered into the database once a year for each patient. Using the database, a study was undertaken to elucidate the relationship between nutrition and lung function in a large patient cohort by cross sectional and longitudinal analysis.
A cohort of 3298 patients above 2 years of age was analysed. Patients were grouped according to the presence or absence of malnutrition (wasting and/or stunting). Cross sectional and longitudinal analyses over 2 and 3 years including mixed model analyses were performed.
The prevalence of abnormal weight for height (<90% predicted) increased with age from 19% in children aged <6 years to 38% in adults with CF. Patients with malnutrition had significantly lower mean values of vital capacity, arterial oxygen tension (PO(2)), and forced expiratory volume in 1 second (FEV(1)) and higher serum IgG (p<0.05). Pseudomonas aeruginosa infection was also associated with decreased pulmonary function. Malnourished adolescents aged 12-18 years experienced a serious decline in FEV(1) of about 20% predicted, whereas mean FEV(1) values remained stable at above 80% predicted in adolescents of normal weight. Longitudinal follow up showed that malnourished patients of all ages and those with P aeruginosa infection had significantly worse lung function than their normally nourished counterparts and a greater yearly loss of FEV(1) % predicted. During 1 year of observation adolescents who experienced a >5% predicted decrease in weight for height had a concomitant mean loss of FEV(1) of 16.5% predicted during that year, whereas patients who gained relative weight had a parallel increase in FEV(1) of 2.1% predicted.
These data emphasise the close relationship between nutrition, lung function, and clinical course in CF. Normal body weight and absence of P aeruginosa infection was associated with better preservation of lung function.
For effective clinical management of cystic fibrosis (CF) lung disease it is important to closely monitor the start and progression of lung damage. The aim of this study was to investigate the ability of high-resolution computed tomography (HRCT) scoring systems and pulmonary function tests (PFT) to detect changes in lung disease. CF children (n=48) had two HRCT scans in combination with two PFT 2 yrs apart. Their scans were scored using five scoring systems (Castile, Brody, Helbich, Santamaria and Bhalla). "Sensitivity" was defined as the ability to detect disease progression. In this group of children, HRCT scores worsened. PFT remained unchanged or improved. Of the HRCT parameters, mucous plugging and the severity, extent and peripheral extension of bronchiectasis worsened significantly. Relationships between changes in HRCT scores and PFT were weak. Substantial structural lung damage was evident in some children who had normal lung function. These data show that high-resolution computed tomography is more sensitive than pulmonary function tests in the detection of early and progressive lung disease, and suggest that high-resolution computed tomography may be useful in the follow up of cystic fibrosis children and as an outcome measure in studies that aim to reduce lung damage.
Polymorphisms in genes other than the cystic fibrosis transmembrane conductance regulator (CFTR) gene may modify the severity of pulmonary disease in patients with cystic fibrosis.
We performed two studies with different patient samples. We first tested 808 patients who were homozygous for the DeltaF508 mutation and were classified as having either severe or mild lung disease, as defined by the lowest or highest quartile of forced expiratory volume in one second (FEV1), respectively, for age. We genotyped 16 polymorphisms in 10 genes reported by others as modifiers of disease severity in cystic fibrosis and tested for an association in patients with severe disease (263 patients) or mild disease (545). In the replication (second) study, we tested 498 patients, with various CFTR genotypes and a range of FEV1 values, for an association of the TGFbeta1 codon 10 CC genotype with low FEV1.
In the initial study, significant allelic and genotypic associations with phenotype were seen only for TGFbeta1 (the gene encoding transforming growth factor beta1), particularly the -509 and codon 10 polymorphisms (with P values obtained with the use of Fisher's exact test and logistic regression ranging from 0.006 to 0.0002). The odds ratio was about 2.2 for the highest-risk TGFbeta1 genotype (codon 10 CC) in association with the phenotype for severe lung disease. The replication study confirmed the association of the TGFbeta1 codon 10 CC genotype with more severe lung disease in comparisons with the use of dichotomized FEV1 for severity status (P=0.0002) and FEV1 values directly (P=0.02).
Genetic variation in the 5' end of TGFbeta1 or a nearby upstream region modifies disease severity in cystic fibrosis.
The study of genetic modifiers in cystic fibrosis (CF) lung disease requires rigorous phenotyping. One type of genetic association study design compares polymorphisms in patients at extremes of phenotype, requiring accurate classification of pulmonary disease at varying ages.
To evaluate approaches to quantify severity of pulmonary disease and their ability to discriminate between patients with CF at the extremes of phenotype.
DeltaF508 homozygotes (n = 828) were initially classified as "severe" (approximate lowest quartile of FEV(1) (% pred) for age, 8-25 yr) or "mild" disease (highest quartile of FEV(1) for age, > or = 15 yr). FEV(1) measurements from the 5 yr before enrollment (total = 18,501 measurements; average 23 per subject) were analyzed with mixed models, and patient-specific estimates of FEV(1) (% pred) at ages 5, 10, 15, 20, and 25 yr and slope of FEV(1) versus age were examined for their ability to discriminate between groups using receiver operating characteristics (ROC) curve areas.
Logistic regression of severity group on mixed model (empirical Bayes) estimates of intercept and slope of FEV(1) (% pred) versus age discriminated better than did classification using FEV(1) slope alone (ROC area = 0.995 vs. 0.821) and was equivalent to using estimated FEV(1) at 20 yr of age as a single discriminator. The estimated survival percentile from a joint survival/longitudinal model provided equally good classification (ROC area = 0.994).
In CF, estimated FEV(1) (% pred) at 20 yr of age and the estimated survival percentile are useful indices of pulmonary disease severity.
Cystic fibrosis (CF) is a complex illness characterized by chronic lung infection leading to deterioration in function and respiratory failure in over 85% of patients. An understanding of the risk factors for that progression and the interaction of these factors with current therapeutic strategies should materially improve the prevention of this progressive lung disease. The Epidemiologic Study of Cystic Fibrosis (ESCF) was therefore designed as a multicenter, longitudinal, observational study to prospectively collect detailed clinical, therapeutic, microbiologic, and lung function data from a large number of CF treatment sites in the U.S. and Canada. The ESCF also serves an important role as a phase-IV study of dornase alfa. To be eligible for enrollment, subjects must have the diagnosis of CF and receive the majority of their care at an ESCF site.In this paper, the authors present the ESCF study design in detail. Further, enrollment data collected at 194 study sites in 18,411 subjects enrolled from December 1, 1993 to December 31, 1995 are presented in summary form. This comprehensive study is unique in the detail of clinical data collected regarding patient monitoring and therapeutic practices in CF care. Two companion articles present data regarding practice patterns in cystic fibrosis care, including data on resource utilization and prescribing practices. Pediatr Pulmonol. 1999; 28:231–241. © 1999 Wiley-Liss, Inc.
The pulmonary function records of 132 patients with cystic fibrosis followed for 5 to 7 years were reviewed. Changes in forced vital capacity, 1-sec forced expiratory volume, mean forced expiratory flow during the middle half of the forced vital capacity, and 1-sec forced expiratory volume as a percentage of forced vital capacity were examined. There was considerable variation in the rates of change, but the general pattern was consistent with a theory of exponential decline, mean forced expiratory flow during the middle half of the forced vital capacity showing the earliest and most dramatic changes. The pulmonary function of 33 patients (25 per cent) remained stable or improved throughout follow-up, possibly reflecting mild forms of lung disease or the efficacy of therapy. Twenty of these patients (15 per cent) maintained completely normal pulmonary function. The rate of decline in pulmonary function values, with progress of the disease, was steeper in the female patients.
To evaluate the relationship between Pseudomonas aeruginosa colonization and the development of lung disease, we studied 895 patients who attended our cystic fibrosis clinic between 1975 and 1988. The prevalence of P. aeruginosa colonization was 82%. Patients who acquired P. aeruginosa in the first year of life had a similar 10-year survival rate (85%) to that in patients who were colonized between the ages of 1 and 7 years (87%), and to that in patients colonized after the age of 7 years (78%). One year before colonization, mean age, forced expiratory volume in 1 second (FEV1), forced vital capacity, and forced expiratory flow in the mid-expiratory phase were similar to those in a group of patients who remained free of P. aeruginosa. No significant change in pulmonary function variables could be demonstrated 1 year and 2 years after the colonization. The rate and duration of hospitalization did not increase in the years after P. aeruginosa colonization compared with the years before colonization. By the age of 7 years, the mean percentage of predicted FEV1 was lower by 10% in patients who were already colonized by P. aeruginosa compared with those who were not colonized (p less than 0.01). A similar reduction in FEV1 was observed at all ages from 7 to 35 years, but no precipitate rate of decline in FEV1 could be associated with P. aeruginosa colonization. We conclude that although P. aeruginosa colonization is associated with 10% lower lung function, it does not cause an immediate and rapid reduction, as has been previously reported. The clinical course and the pulmonary deterioration in cystic fibrosis after P. aeruginosa colonization is a gradual and variable process.
We conducted a historical prospective study of 124 cystic fibrosis (CF) patients colonized with Pseudomonas cepacia (cases) and 124 sex and age matched non-colonized CF patients (controls). Thirty-two of the colonized patients died in the first year following P. cepacia colonization compared to 8 of the control patients, a highly significant difference (p less than 0.001). In the second year, there was no significant difference in mortality between the two groups. Cases as a group had poorer pulmonary function and chest X-ray scores than controls up to 2 years before P. cepacia first appeared in their sputum or throat cultures. Regression analysis of pulmonary function tests (percent predicted FEV1 and RV/TLC) for each subject from 3 years before to 2 years after colonization revealed significant differences between cases and controls in slope for FEV1 and in slope and intercept for RV/TLC. When compared separately according to gender, the differences between cases and controls are significant in females but not in males. These results suggest that patients with poor pulmonary function are more prone to colonization with P. cepacia, that a subgroup of these patients will be dramatically affected and die within a year, and that the organism continues to exert a less dramatic negative effect on the pulmonary function of those patients who survive the initial acute effects of colonization, particularly in female patients.
Because of the time and the emotional cost involved in performing daily conventional chest physiotherapy in patients with cystic fibrosis, a 3-year prospective study was undertaken to compare the long-term effects of postural drainage accompanied by percussion and the forced expiratory technique with the effects of the forced expiratory technique alone. Patients who performed the forced expiratory technique alone had mean annual rates of decline that were significantly different from zero for forced expiratory volume in 1 second (p less than 0.001), forced expiratory flow between 25% and 75% of vital capacity (p less than 0.001), and Shwachman clinical score (p less than 0.004). In the group performing conventional physiotherapy with percussion and postural drainage, only the mean annual rate of decline for forced expiratory flow between 25% and 75% of vital capacity was significantly different from zero (p less than 0.03), and it was significantly different from the mean rate of decline associated with the forces expiratory technique alone (p less than 0.04). We conclude that conventional chest physiotherapy should remain a standard component of therapy in cystic fibrosis.
In a two-year prospective study, we examined the effect of respiratory viral infections on pulmonary function in 49 patients with cystic fibrosis (mean age, 13.7 years). Nineteen normal siblings (mean age, 14) served as controls. Subjects were assessed quarterly and at the time of any respiratory illness. Each assessment included nasal washes for viral isolation and blood drawing for respiratory viral serologic studies. Pulmonary-function tests were performed at least twice yearly. Respiratory illnesses were reported significantly more often in the patients (3.7 per year) than in the normal siblings (1.7 per year), although the frequency of proved viral infections (1.67 per year) was identical. In the patients with cystic fibrosis significant correlations (P less than 0.0001) were found between the annual incidence of viral infections and every measure of disease progression in the two-year period, including the rate of decline of the Shwachman score (r = 0.71), the percentage of ideal weight for height (r = 0.80), the forced vital capacity (r = 0.85), the forced expiratory volume in the first second (r = 0.84), the forced midexpiratory flow rate (r = 0.68), and the frequency (r = 0.53) and duration (r = 0.84) of hospitalizations for respiratory exacerbations. We conclude that frequency of viral respiratory infections is closely associated with pulmonary deterioration in patients with cystic fibrosis.
The median survival age for females with cystic fibrosis (CF) is approximately 3 years younger than for males. We tested whether earlier acquisition of Pseudomonas aeruginosa (PA) by female CF patients or the greater impact of this organism on their lung disease, or both, contribute to their poorer survival. PA infection status, survival, pulmonary function tests, and chest X-ray scores from patients who were followed at our center for at least 2 years with a minimum of three respiratory cultures per year were analyzed (n = 848). The median age of chronic infection with mucoid PA was 1.7 years earlier in females than in males. Patients infected with mucoid PA had poorer survival, chest X-ray scores, and pulmonary function tests than patients who had either no Pseudomonas species or only the nonmucoid phenotype. Acquisition of mucoid PA was associated with an accelerated rate of decline in pulmonary function. However, the rate of change of pulmonary function after mucoid PA infection was similar for males and females. Moreover, even among patients who had only the mucoid form or only the nonmucoid form, males had better percent predicted forced expiratory volume in 1 sec and better survival. Therefore, factors in addition to earlier acquisition of mucoid PA may contribute to the poorer survival of female CF patients.
To determine the extent of airway infection and inflammation in adolescents and adults with cystic fibrosis (CF) who have mild lung disease and are without symptoms of active infection, we performed bronchoalveolar lavage (BAL) on 18 CF patients > or = 12 yr of age who were stable, appeared clinically well, and had mean (+/- SEM) FEV1 of 79 +/- 4% of predicted. We quantitated the bacteria, inflammatory cells, immunoglobulins, and mediators of inflammatory tissue damage in the epithelial lining fluid (ELF) of these patients and in 23 healthy control subjects. All CF patients were found to be infected with Pseudomonas aeruginosa, Staphylococcus aureus, and/or Haemophilus influenzae; no organisms were isolated from the control subjects. The mean number of cells in the ELF was 14 times greater in the CF patients than in the control subjects. Neutrophils constituted 57% of the recovered cells in the CF patients versus 3% in the control subjects, and their concentration was 380 times greater in the CF patients versus the control subjects. IgG, IgA, and IgM were 2.5 to 6 times greater in CF ELF versus that of control subjects. Abundant active elastase was present in the ELF of the CF patients (2.3 +/- 0.9 microM) despite threefold elevated levels of alpha 1-protease inhibitor (alpha 1-PI). No active elastase was detectable in the control subjects. alpha 1-PI was functional in CF as demonstrated by elevated elastase:alpha 1-PI complex (0.045 microM in CF versus 0.002 microM in control subjects). This active elastase caused proteolytic destruction of surface complement receptors on airway neutrophils in situ.(ABSTRACT TRUNCATED AT 250 WORDS)
Pulmonary function of children aged 6-18 years is described based on 82,462 annual measurements of forced vital capacity (FVC), forced expired volume in 1 second (FEV1), and forced expiratory flow between 25% and 75% of FVC (FEF25-75%) from 11,630 white children and 989 black children. Median height, FVC, FEV1, FEV1/FVC, and FEF25-75% for each 3 months of age are compared among race and sex subgroups. Race- and sex-specific percentile distributions of FVC, FEV1, FEV1/FVC, and FEF25-75% are presented for each centimeter of height (growth curves). For the same height, boys have greater lung function values than girls, and whites have greater ones than blacks. Lung function increases linearly with age until the adolescent growth spurt at about age 10 years in girls and 12 in boys. The pulmonary function vs. height relationship shifts with age during adolescence. Thus, a single equation or the pulmonary function-height growth chart alone does not completely describe growth during the complex adolescent period. Nevertheless, race- and sex-specific growth curves of pulmonary function vs. height make it easy to display and evaluate repeated measures of pulmonary function for an individual child. Race-, sex-, and age-specific regression equations based on height are provided, which permit the evaluation of growth during adolescence with improved accuracy and, more importantly, in comparison with previous observations for the same child.
Growth failure and malnutrition are common clinical features in cystic fibrosis (CF), but the relationships among resting energy expenditure (REE), pulmonary function, and nutritional status, are poorly understood. To better understand these relationships, REE, growth, nutritional status, and pulmonary function were measured prospectively in 25 prepubertal children with CF and 26 prepubertal control subjects of similar age and gender over a 3-y period. All subjects with CF had pancreatic insufficiency and mild pulmonary disease. REE was elevated for the CF children compared with control subjects throughout the study. This increased REE was not associated with declining pulmonary function. Longitudinal analyses revealed different patterns of change over time in boys and girls, such that REE significantly increased in the girls with CF and pulmonary function decreased in the boys. Boys with CF experienced a decline in weight Z score and percent ideal body weight, whereas the girls with CF experienced a decline in height Z score. Pulmonary function was not associated with REE, but nutritional status (percent ideal body weight) and genotype (delta F508 homozygotes versus others) were predictive of changes in pulmonary function over time. Fat free mass and height were found to be the best predictors of REE, and after accounting for these important body size and composition variables, differences in REE between boys and girls and CF and control groups increased over time. These findings identify the importance of investigating gender differences in the course of disease and considering REE as an early indicator of disease severity independent of pulmonary function.
Rapid progress in cystic fibrosis research affords the possibility of halting the progress of the lung disease. We used data from 215 patients who had sputum cultures negative for Burkholderia cepacia, at least one outpatient pulmonary function test during 1990, and at least one test a year later to estimate the number of subjects and study duration required to demonstrate that a hypothetical treatment reduces the rate of decline of forced expiratory volume in 1 s (FEV1) to zero. Mean rate of decline of FEV1 (percent predicted) was about 2% predicted per year. Variability decreases with increasing time of observation. For a 1-y study, with alpha = 0.05 and beta = 0.20, over 550 patients must complete the study in each group to show that a treatment halts pulmonary decline. For a 2-y study, 86 subjects in each group are required, and for 4 y, 65. Increasing the number of data points used to determine the rate of decline of FEV1 had only small effect on sample size. Use of pulmonary function data collected at regular intervals for research purposes did not alter these conclusions. Higher initial FEV1 was associated with a greater rate of decline, and among patients with initial FEV1 > 60% predicted, younger subjects had a faster decline than did older subjects. Thus, fewer subjects will be required to detect a complete halt in progression of lung disease if the patients are young and have mild pulmonary disease.
Chronic progressive lung disease is the most prominent cause of morbidity and death in patients with cystic fibrosis (CF), but severity of lung disease and rate of lung function decline are widely variable. Accurate estimates of decline have been difficult to define and compare because the timing of measurements and duration of follow-up differ in various patient groups.
Three hundred sixty-six patients with CF, born from 1960 to 1974, were selected from a CF database birth cohort if they had two or more measurements of pulmonary function, at least one of which was performed before the age of 10 years.
Mixed model regression analysis provided estimates of the average rate of decline of spirometry measurements in subgroups on the basis of survival age, sex, pancreatic status, and genotype.
Patients who died before the age of 15 years had significantly poorer pulmonary function when first tested and a more rapid decline in pulmonary function thereafter than patients who survived beyond the age of 15 years. In the latter, functional levels at the age of 5 years were normal, but average rates of decline were significantly related to survival age. Female patients had significantly steeper decline than male patients, and those with pancreatic insufficiency had much steeper decline than those with pancreatic sufficiency. In the subset of 197 who survived to 1990 and were subsequently genotyped, rate of decline was greater in those homozygous for the delta F508 mutation, compared with those who were heterozygous for delta F508 or those, who had two other mutations.
All but the most severely affected patients, who died before age 15, appear to have had normal pulmonary function when first tested in early childhood. Pancreatic sufficiency, male gender, and some non-delta F508 mutations are associated with a slower rate of pulmonary function decline. Mixed model analysis is a valuable tool for describing and comparing pulmonary function decline in groups of patients with CF.
Cystic fibrosis (CF) is a complex illness characterized by chronic lung infection leading to deterioration in function and respiratory failure in over 85% of patients. An understanding of the risk factors for that progression and the interaction of these factors with current therapeutic strategies should materially improve the prevention of this progressive lung disease. The Epidemiologic Study of Cystic Fibrosis (ESCF) was therefore designed as a multicenter, longitudinal, observational study to prospectively collect detailed clinical, therapeutic, microbiologic, and lung function data from a large number of CF treatment sites in the U.S. and Canada. The ESCF also serves an important role as a phase-IV study of dornase alfa. To be eligible for enrollment, subjects must have the diagnosis of CF and receive the majority of their care at an ESCF site. In this paper, the authors present the ESCF study design in detail. Further, enrollment data collected at 194 study sites in 18,411 subjects enrolled from December 1, 1993 to December 31, 1995 are presented in summary form. This comprehensive study is unique in the detail of clinical data collected regarding patient monitoring and therapeutic practices in CF care. Two companion articles present data regarding practice patterns in cystic fibrosis care, including data on resource utilization and prescribing practices.
To evaluate the effects of a 3-year home exercise program on pulmonary function and exercise tolerance in mildly to moderately impaired patients with cystic fibrosis (CF) and to assess whether regular aerobic exercise is a realistic treatment option.
Seventy-two patients with CF (7-19 years) were randomly assigned to an exercise group (a minimum of 20 minutes of aerobic exercise, at a heart rate of approximately 150 beats/min, 3 times weekly) or a control group (usual physical activity participation). Pulmonary function, exercise tolerance, clinical status, hospitalizations, and compliance with therapy were monitored during scheduled visits to the hospital's CF clinic.
Sixty-five patients were included in the analyses. The control group demonstrated a greater annual decline in percent of predicted forced vital capacity compared with the exercise group (mean slope +/- SD, -2.42 +/- 4.15 vs -0.25 +/- 2.81; P =.02), with a similar trend for forced expiratory volume in 1 second (-3.47 +/- 4.93 vs -1.46 +/- 3. 55; P =.07). Patients remained compliant with the exercise program over the study period. An improved sense of well-being was reported with exercise.
Pulmonary function declined more slowly in the exercise group than in the control group, suggesting a benefit for patients with CF participating in regular aerobic exercise. Consistent compliance with the home exercise program and a self-reported positive attitude toward exercise provide further evidence of the feasibility and value of including an aerobic exercise program in the conventional treatment regimen of patients with CF.
To determine prospectively the relationship among growth, nutritional status, and pulmonary function over a 4-year period in a large cohort of children with cystic fibrosis (CF).
CF Foundation National CF Patient Registry data collected from 1991 to 1995 for 968 children (507 male) aged 5 to 8 years with pancreatic insufficiency and forced expiratory volume in 1 second within 60% to 140% of predicted values (FEV(1)%) were analyzed longitudinally. Variables hypothesized to affect FEV(1)% included age, sex, z scores for height, weight, percent of height-appropriate body weight, and annual number of days hospitalized.
The significant decline in FEV(1)% was curvilinear and dependent on baseline FEV(1)%; children with initial FEV(1)% > or = 90 declined 2.6 U/y more than those with initial FEV(1)% <90. Boys gained but girls declined in z scores for height. Girls decreased in z scores for weight at a greater rate than boys. The z scores for weight and percent of height-appropriate body weight were significantly associated with longitudinal changes in FEV(1)%, after adjustment was done for hospitalizations.
Growth, nutritional status, and pulmonary function are not stable in prepubertal children with CF and pancreatic insufficiency. Important sex-related differences in growth occur before puberty. Growth and nutritional status are associated with changes in FEV(1)%, suggesting that nutritional intervention may slow the decline in pulmonary function in children with CF.
In patients with cystic fibrosis, CF-related diabetes mellitus (CFRD) has been associated with increased morbidity and mortality. Whether glucose intolerance is also associated with poor outcomes is unclear. To better define these relationships we prospectively followed a group of 152 patients with CF without diabetes for 4 yr. Patients were classified as having normal glucose tolerance (NGT), impaired glucose tolerance (IGT), or CFRD without fasting hyperglycemia (CFRD-No FH). FEV(1), FVC, and body mass index (BMI) were measured at baseline and quarterly. At baseline 45% of the patients had NGT, 38.8% had IGT, and 15.8% had CFRD-No FH. FEV(1), FVC, and BMI at baseline were comparable among these groups (all p > 0.1). After 4 yr an overall decline in FEV(1) and FVC occurred, with no change in BMI. The rates of decline for FEV(1) and FVC correlated with the glucose tolerance groups, with the highest rates of decline occurring among the CFRD-No FH group. In addition, patients in the lowest quartile for insulin production at baseline experienced the highest rates of pulmonary function decline over time, suggesting a relationship between insulin deficiency and clinical deterioration. We conclude that the degree of glucose intolerance is a strong determinant of future lung function decline in patients with CF.
Modelling the relationship between pulmonary function and survival in cystic fibrosis (CF) is complicated by the fact that measures of pulmonary function commonly used such as the forced expiratory volume in one second (FEV(1)) are measured with error, and patients with the poorest lung function are increasingly censored by death, that is, data are available only for the patients who have survived to the current age. We assume a linear random effects model for FEV1 per cent predicted, where the random intercept and slope of FEV(1) per cent predicted, along with a specified transformation of the age at death follow a trivariate normal distribution. We illustrate how this model can be used to describe the relationship between age at death and parameters of the individual patient's regression of FEV(1) per cent predicted versus age, such as the slope and the intercept or true value of FEV(1) per cent predicted at a given age. We also illustrate how the model provides empirical Bayes estimates of these individual parameters. In particular, we explore how the predicted value of the age at death might be used as a prognostic or severity index. The model and methods are illustrated on a cohort of 188 cystic fibrosis patients with a common genotype (homozygous for the DeltaF508 mutation), born on or after 1965 and followed at the CF Center at the Rainbow Babies and Children's Hospital, Cleveland, OH, U.S.A.
The Epidemiologic Study of Cystic Fibrosis: risk factors for FEV1 decline in children and adolescents with CF
- Konstan
Konstan MW, Butler S, Stoddard M, Zheng B, Morgan WJ. The Epidemiologic Study of Cystic Fibrosis: risk factors for FEV 1 decline in children and adolescents with CF. Pediatr Pulmonol 2001(suppl 22):322.
); Department of Pediatrics, Children's Hospital at Dart-mouth and Dartmouth Medical School
- Specialty Biotherapeutics
- Genentech
- Inc
- San South
- S B Francisco
- Ovation Group
Specialty Biotherapeutics, Genentech, Inc., South San Francisco (S.B., M.C., J.W., C.J.), and Ovation Research Group, San Fran-cisco, California (D.P., S.S.); Department of Pediatrics, Children's Hospital at Dart-mouth and Dartmouth Medical School, Lebanon, New Hampshire (D.S.);
Children's Hospital and Harvard Medical School Department of Pediatrics, The Children's Hospital and University of Col-orado School of Medicine
- Dept
Dept. of Pediatrics, Children's Hospital and Harvard Medical School, Boston, Massachusetts (M.W.); Department of Pediatrics, The Children's Hospital and University of Col-orado School of Medicine, Denver, Colo-rado (J.W.);
Submitted for publication Reprint requests: Michael W. Konstan, MD, Rainbow Babies and Children's Hospital E-mail: michael.konstan@case.edu. *List of members available at www.jpeds. com. 0022-3476/$ -see front matter Copyright © 2007 Mosby Inc. All rights reserved
- Supported
- Genentech
- Inc
- San South
- Francisco
- Calif
Supported by Genentech, Inc., South San Francisco, Calif. Submitted for publication Jun 30, 2006; last revision received Dec 1, 2006; accepted Mar 5, 2007. Reprint requests: Michael W. Konstan, MD, Rainbow Babies and Children's Hospital, 11100 Euclid Ave, Cleveland, OH 44106. E-mail: michael.konstan@case.edu. *List of members available at www.jpeds. com. 0022-3476/$ -see front matter Copyright © 2007 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2007.03.006 REFERENCES
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- Ruben Budhecha
- Diaz
Arkansas — John Carroll, Robert Warren, Louay Nassri, Paula Anderson; Arizona — Mark Brown, Amy Silverthorn, Peggy Radford, Gerald Gong, Gregory Legris; California — Gerald Greene, Reddivalam Sudhakar, Arnold Platzker, Bruce Nickerson, Karen Hardy, Ivan Harwood, Gregory Shay, Bryon Quick, Allan Lieberthal, Richard Moss, Chris Landon, Yvonne Fanous, Jay Lieberman, Eugene Spiritus, Bradley Chipps, Ruth McDonald, Mark Pian, Gerd Cropp, Nancy Lewis, Dennis Nielson, Bertrand Shapiro; Colorado — Jeff Wagener, Frank Accurso, Milene Saavedra; Connecticut — Karen Daigle, Jacob Hen, Regina Palazzo; Delaware — Kathryn Dodds, Raj Padman, John Goodill; District of Co-lumbia — Glenna Winnie, Lea Davies; Florida — Tony Kriseman, Jorge Sallent, Joseph Chiaro, Martin Kubiet, Sue Goldfinger, Morton Schwartzman, Carlosenrique Diaz, Kevin Maupin, Eduardo Riff, David Geller, Floyd Living-ston, Kunjana Mavunda, Jose Birriel, Jr., Luis Faverio, David Rosenberg, David Schaeffer, James Sherman, Mary Wagner, Michael Light, Bruce Schnapf; Georgia — Gary Montgom-ery, Kevin Kirchner, Mark Weatherly, Daniel Caplan, Mar-garet Guill, Valera Hudson; Illinois — Javeed Akhter, Donald Davison, Steven Boas, Susanna McColley, Youngran Chung, Rennee Latner, Gabriel Aljadeff, Youngran Chan, Jerome Kraut, Arvey Stone, John Lloyd Still, Girish Sharma, Lanie Eagleton, Patricia Hopkins, Umesh Chatrath, Lucille Lester, Young-Jee Kim; Indiana — Veena Anthony, Howard Eigan, Michelle Howenstine, Pushpom James, Edward Gergesha, James Harris, Robert Plant; Iowa — Veljko Zivkovich, An-gela Collins, Edward Nassif, Richard Ahrens; Kansas — Daniel Doornbos, Joseph Kanarek, Richard Leff, Pamela Shaw, Elanor Demoss, Maria Riva, Leonard Sullivan; Ken-tucky — Michael Anstead, Jamshed Kanga, Nemr Eid, Ron Morton; Louisana — Bettina Hilman, Kim Jones, Scott Davis; Maine — Ralph Harder, Tom Lever, Anne Marie Cairns, Edgar Caldwell, Jonathan Zuckerman; Maryland — Peter Mogayzel, Beryl Rosenstein, John McQuestion, Donna Perry, Samuel Rosenberg; Massachusetts — Robert Gerstle, Andrew Colin, Mary Ellen Wohl, Allan Lapey, William Yee, Brian O'Sullivan, Robert Zwerdling; Michigan — Ibrahim Abdulhamid, Adrian O'Hagan, John Schuen, Lawrence Kur-landsky, Richard Honicky, Douglas Homnick, John Marks, Bohdan Pichurko, Norma Maxvold, Samya Nasr, Richard Simon, Wan Tsai, Dana Kissner; Minnesota — John Mc-Namara, Nancy Henry, Stephen Marker, Michael Pryor, Warren Regelmann, Lynn Walker; Mississippi — Jim Wood-ward, Louis Mizell, Suzanne Miller; Missouri — Daniel Rosenbluth, Philip Black, Michael McCubbin, Alan Cohen, Thomas Ferkol, George Mallory, Anthony Rejent, Bruce Rubin, Gavin Graff, Peter Konig; Nebraska — John Co-lombo, Peter Murphy; New Hampshire — William Boyle, H. Worth Parker; New Jersey — Chandler Patton, Robert Zanni, Arthur Atlas, Nelson Turcios, Lourdes Laraya-Cuasay, Do-rothy Bisberg, Helen Aguila; New Mexico — Sarah Allen, David James, Elizabeth Perkett, Marsha Thompson; Nevada — Sonia Budhecha, Ruben Diaz; New York — Jonathan Rosen, Robert Kaslovsky, Ronald Percciacante, Drucy Borowitz, Joseph Cronin, Colin McMahon, Lynne Quittell, Robert Giusti, Rubin Cohen, Joan DeCelie-Germana, Jack Gorvoy, Kalpan Patel, Meyer Kattan, Allen Dozor, Emily DiMango, Maria Berdella, Ran Anbar, Debra Ianuzzi, James Sexton, Catherine Tayag-Kier, John McBride, Clement Ren, Karen Voter, Mary Dimaio; North Carolina — Gerald Geor-gitis, Joseph Marc Majure, Maria Martinez, J. Clarke McIn-tosh, Margaret Leigh, Michael Schechter, Hugh Black; North Dakota — James Hughes, Anand Kantak; Ohio — Robert Wilmott, Gregory Omlor, Robert Stone, Karen McCoy, James Acton, Carl Doershuk, Michael Konstan, Robert Fink, Michael Steffan, Pierre Vauthy, Patricia Joseph; Oklahoma — Santiago Reyes, John Kramer, James Royall; Oregon — Jay Eisenberg, Michael Wall; Pennsylvania — Stanley Fiel, Thomas Scanlin, Shroti Phadke, Glenna Winnie, Joel Wein-berg, William Sexauer, Stephen Wolf, Douglas Holsclaw, Debra Klein, W. Stuart Warren, Robert Kinsey, Carlos Perez, Muttiah Ganeshanathan, James Shinnick, Howard Panitch, Laurie Varlotta, Cynthia Robinson; Puerto Rico — Jose Rodriguez Santana; Rhode Island — Mary Ann Passero;
- Nj Johnson
- K Dodd
Johnson NJ, Dodd K. J Pediatr 1957;51:190-3