Clement L. Ren

An Official American Thoracic Society Workshop Report: Optimal Lung Function Tests for Monitoring Cystic Fibrosis, Bronchopulmonary Dysplasia, and Recurrent Wheezing in Children Less Than 6 Years of Age

Although pulmonary function testing plays a key role in the diagnosis and management of chronic pulmonary conditions in children under 6 years of age, objective physiologic assessment is limited in the clinical care of infants and children less than 6 years old, due to the challenges of measuring lung function in this age range. Ongoing research in lung function testing in infants, toddlers, and preschoolers has resulted in techniques that show promise as safe, feasible, and potentially clinically useful tests. Official American Thoracic Society workshops were convened in 2009 and 2010 to review six lung function tests based on a comprehensive review of the literature (infant raised-volume rapid thoracic compression and plethysmography, preschool spirometry, specific airway resistance, forced oscillation, the interrupter technique, and multiple-breath washout). In these proceedings, the current state of the art for each of these tests is reviewed as it applies to the clinical management of infants and children under 6 years of age with cystic fibrosis, bronchopulmonary dysplasia, and recurrent wheeze, using a standardized format that allows easy comparison between the measures. Although insufficient evidence exists to recommend incorporation of these tests into the routine diagnostic evaluation and clinical monitoring of infants and young children with cystic fibrosis, bronchopulmonary dysplasia, or recurrent wheeze, they may be valuable tools with which to address specific concerns, such as ongoing symptoms or monitoring response to treatment, and as outcome measures in clinical research studies.

Treatment complexity in cystic fibrosis: trends over time and associations with site-specific outcomes.

BACKGROUND Patients with cystic fibrosis (CF) have increasing treatment complexity and high treatment burden. We describe trends in treatment complexity and evaluate its relationship with health outcomes. METHODS Using Epidemiologic Study of Cystic Fibrosis (ESCF) data, we developed a treatment complexity score (TCS) from 37 chronic therapies and assessed change by age group (6-13, 14-17, and 18+ years) over a three year period. Differences in average site TCS were evaluated by quartiles based on FEV1, BMI, or Treatment Burden score on the Cystic Fibrosis Questionnaire-Revised (CFQ-R). RESULTS TCS scores were calculated for 7252 individual patients (42% child, 16% adolescent, 43% adult) across 153 sites. In 2003, mean TCS was 11.1 for children, 11.8 for adolescents, and 12.1 for adults. In all 3 age groups, TCS increased over 3 years; the increase in TCS from 2003-2005 for children was 1.25 (95% CI 1.16-1.34), for adolescents 0.77 (0.62-0.93), and for adults 1.20 (1.08-1.31) (all P<0.001 for trend over time). At the site level, there were no significant differences in mean TCS based on FEV1 quartile. Mean TCS was higher in the highest BMI z-score quartile. Across all 3 versions of the CFQ-R, mean TCS was lower at sites in the highest quartiles (lowest burden) for CFQ-R treatment burden scores. CONCLUSION Treatment complexity was highest among adults with CF, although over 3 years, we observed a significant increase in treatment complexity in all age groups. Such increases in treatment complexity pose a challenge to patient self-management and adherence. Future research is needed to understand the associations between treatment complexity and subsequent health outcomes to reduce treatment burden and improve disease management.

The impact of incident methicillin resistant Staphylococcus aureus detection on pulmonary function in cystic fibrosis

The incidence of methicillin resistant Staphylococcus aureus (MRSA) infection is increasing in cystic fibrosis (CF), but the impact of MRSA detection on clinical outcomes is unclear. Our objective was to determine whether incident detection of MRSA is associated with a change in pulmonary function over time in CF patients. We analyzed data from the Epidemiologic Study of Cystic Fibrosis (ESCF), a prospective observational study of CF patients in North America. Multivariable piecewise linear regression was used to model the impact of incident detection of MRSA on pulmonary function over time, measured by percent predicted forced expiratory volume in one second (FEV1% predicted), adjusting for potential confounders. There were 5,090 patients ≥6 years old who were MRSA negative for at least 2 calendar years. Five hundred ninety‐three (12%) of these patients acquired MRSA during the years 2001–2003, with detection rates of MRSA during those years rising from 4.4% to 6.9%. MRSA positive patients had a lower FEV1% predicted and received more antibiotic and other therapies than patients who remained MRSA negative. After adjusting for antibiotic therapy and other potential confounders, MRSA positive patients also had a higher rate of decline in FEV1% predicted both before and after the incident culture, although the rate of FEV1% predicted decline did not change significantly after MRSA detection. In conclusion, although MRSA in CF was a marker for more aggressive therapy and may reflect increased disease severity, incident MRSA detection was not associated with a changing rate of FEV1% predicted decline. Pediatr. Pulmonol. 2008; 43:1117–1123.

Relationship between Inhaled Corticosteroid Therapy and Rate of Lung Function Decline in Children with Cystic Fibrosis

OBJECTIVE To assess the relationship between inhaled corticosteroids (ICS) use and lung function decline in children with cystic fibrosis (CF) using the Epidemiologic Study of Cystic Fibrosis, an observational study of patients with CF in North America. STUDY DESIGN We analyzed data from 2978 patients 6 to 17 years old enrolled in ESCF between 1994 to 2004. We estimated the rate of decline in forced expiratory volume in 1 second (FEV(1)) before and after starting ICS therapy with a piecewise linear continuous single change point model, adjusting for potentially confounding covariates. RESULTS Before initiation of ICS, mean FEV(1) decline was -1.52% predicted/year (95% CI: -1.96 to -1.08% predicted/year). After initiation of ICS therapy, mean FEV(1) decline was -0.44% predicted/year (95% CI: -0.85 to -0.03% predicted/year), which was a significant change (P = .002). ICS use was associated with decreased height for age Z scores and increased insulin/oral hypoglycemic use. CONCLUSIONS In this retrospective analysis of prospectively collected data, ICS therapy in patients with CF was associated with a significant reduction in the rate of FEV(1) decline, decreased linear growth, and increased insulin/oral hypoglycemic use.

Infant Care Patterns at Epidemiologic Study of Cystic Fibrosis Sites That Achieve Superior Childhood Lung Function

OBJECTIVE. Previous analyses of the Epidemiologic Study of Cystic Fibrosis database revealed that sites with the highest average patient lung function monitor patients and treat with antibiotics more aggressively than those where average lung function is lowest. The aim of this study was to assess whether patterns of care for infants at cystic fibrosis sites with superior average lung function in 6- to 12-year-old children showed any differences from those at the lowest outcome sites. METHODS. We divided cystic fibrosis sites with ≥20 patients who were 6 to 12 years of age into quartiles on the basis of median forced expiratory volume in 1 second of that age group in 2003 and compared demographic and clinical characteristics and treatment patterns during the first year of enrollment for patients who were aged 0 to 3 years at those sites in 1994 to 1999. The analysis included 755 infants from 12 upper quartile sites and 743 infants from 12 lower quartile sites. RESULTS. Upper quartile sites had more infants whose disease was diagnosed by family history or newborn screening, fewer infants with symptoms at diagnosis, higher weight for age at enrollment, more white patients, and more ΔF508 homozygotes. Medical conditions and respiratory tract microbiology differed between sites. Infants at upper quartile sites had more office and sick visits; more respiratory tract cultures; and more frequent use of intravenous antibiotics, oral corticosteroids, mast cell stabilizers, and mucolytics; but they received less chest physiotherapy, inhaled bronchodilators, oral nutritional supplements, and pancreatic enzymes. CONCLUSIONS. Both enrollment characteristics and infant care patterns are associated with lung function outcomes in later childhood. Our analysis suggests that pulmonary function of older children may be improved through specific interventions during the first 3 years of life.

Outcomes of Infants With Indeterminate Diagnosis Detected by Cystic Fibrosis Newborn Screening

BACKGROUND AND OBJECTIVES: Cystic fibrosis transmembrane conductance regulator–related metabolic syndrome (CRMS) describes asymptomatic infants with a positive cystic fibrosis (CF) newborn screen (NBS) but inconclusive diagnostic testing for CF. Little is known about the epidemiology and outcomes of CRMS. The goal of this study was to determine the prevalence, clinical features, and short-term outcomes of infants with CRMS. METHODS: We analyzed data from the US CF Foundation Patient Registry (CFFPR) from 2010 to 2012. We compared demographic, diagnostic, anthropometric, health care utilization, microbiology, and treatment characteristics between infants with CF and infants with CRMS. RESULTS: There were 1983 infants diagnosed via NBS between 2010 and 2012 reported to the CFFPR. By using the CF Foundation guideline definitions, 1540 and 309 infants met the criteria for CF and CRMS, respectively (CF:CRMS ratio = 5.0:1.0). Of note, 40.8% of infants with CRMS were entered into the registry with a clinical diagnosis of CF. Infants with CRMS tended to have normal nutritional indices. However, 11% of infants with CRMS had a positive Pseudomonas aeruginosa respiratory tract culture in the first year of life. CONCLUSIONS: CRMS is a common outcome of CF NBS, and some infants with CRMS may develop features concerning for CF disease. A substantial proportion of infants with CRMS were assigned a clinical diagnosis of CF, which may reflect misclassification or clinical features not collected in the CFFPR.

Baseline Characteristics and Factors Associated With Nutritional and Pulmonary Status at Enrollment in the Cystic Fibrosis EPIC Observational Cohort

The EPIC Observational Study is an ongoing prospective cohort study investigating risk factors for and clinical outcomes associated with early Pseudomonas aeruginosa (Pa) acquisition in young children with cystic fibrosis (CF).

Clinical outcomes in infants with cystic fibrosis transmembrane conductance regulator (CFTR) related metabolic syndrome.

An unavoidable outcome of cystic fibrosis newborn screening (CF NBS) programs is the detection of infants with an indeterminate diagnosis. The United States CF Foundation recently proposed the term cystic fibrosis transmembrane conductance regulator related metabolic syndrome (CRMS) to describe infants with elevated immunoreactive trypsinogen (IRT) on NBS who do not meet diagnostic criteria for CF. The objective of this study was to describe the clinical outcomes of infants with CRMS identified through an IRT/DNA algorithm. We reviewed the records of all infants with CRMS diagnosed at our CF Center from 2002 to 2010. We identified 12 infants, and compared them to 27 infants diagnosed with CF by NBS. Compared to CF patients, CRMS patients were more likely to be pancreatic sufficient as assessed by fecal elastase measurement (100% vs. 8%, P < 0.01). Their weight for age percentile was normal from birth. A positive oropharyngeal (OP) culture for Pseudomonas aeruginosa (Pa) was found in 25% of CRMS patients. One patient with the F508del/R117H/7T genotype was reassigned the diagnosis of CF after he had a positive OP culture for Pa, and his follow up sweat Cl at 1 year of life was 73 mmol/L. CF patients were more likely to receive oral antibiotics and be hospitalized for pulmonary symptoms. Our results indicate that CRMS patients can develop signs of CF disease, but have a milder clinical course than CF infants. Close initial monitoring of these patients is warranted. Pediatr. Pulmonol. 2011; 46:1079–1084.

Risk factors for lung function decline in a large cohort of young cystic fibrosis patients

To identify novel risk factors and corroborate previously identified risk factors for mean annual decline in FEV1% predicted in a large, contemporary, United States cohort of young cystic fibrosis (CF) patients.

Multiple antibiotic-resistant Pseudomonas aeruginosa and lung function decline in patients with cystic fibrosis

BACKGROUND The goal of this study was to determine the association of multiple antibiotic-resistant Pseudomonas aeruginosa (MARPA) acquisition with lung function decline in patients with cystic fibrosis (CF). METHODS Using data from Epidemiologic Study of Cystic Fibrosis (ESCF), we identified patients with spirometry data and MARPA, defined as PA (1) resistant to gentamicin and either tobramycin or amikacin, and (2) resistant to ≥1 antipseudomonal beta lactam. MARPA had to be detected in a respiratory culture after ≥2 years of PA-positive but MARPA-negative respiratory cultures. Multivariable piecewise linear regression was performed to model the annual rate of decline in forced expiratory volume in 1 second (FEV(1)) % predicted 2 calendar years before and after the index year of MARPA detection, adjusting for patient characteristics and CF therapies. RESULTS In total, 4349 patients with chronic PA and adequate PFT data were identified; 1111 subsequently developed MARPA, while 3238 patients were PA positive but MARPA negative. Compared with patients who did not acquire MARPA, MARPA-positive patients had lower FEV(1) and received more oral (p<0.013) and inhaled (p<0.001) antibiotic therapy. Mean FEV(1) decline did not change significantly after MARPA detection (-2.22% predicted/year before detection and -2.43 after, p=0.45). There was no relationship between persistent infection or FEV(1) quartile and FEV(1) decline. CONCLUSIONS Newly detected MARPA was not associated with a significant change in the rate of FEV(1) decline. These results suggest that MARPA is more likely to be a marker of more severe disease and more intensive therapy, and less likely to be contributing independently to more rapid lung function decline.