Papers by Sharon McNamara
American Journal of Respiratory and Critical Care Medicine, 2021
(6), or RNA (7, 8); from measurements of bacterial components such as sputum lipoarabinomannan (9... more (6), or RNA (7, 8); from measurements of bacterial components such as sputum lipoarabinomannan (9); or from genetic epistasis analysis (10). Future clinical trials should test these readouts against each other to better understand their significance. n Author disclosures are available with the text of this letter at www.atsjournals.org. Acknowledgment: The authors thank the study participants and their families. They thank the INHindsight Study Team (A5312 Study Team) members who contributed to the trial.
Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society, Jan 10, 2018
The literature conflicts regarding dental caries risk in cystic fibrosis (CF) relative to control... more The literature conflicts regarding dental caries risk in cystic fibrosis (CF) relative to controls. Prospective, observational study of age-related heterogeneity in caries rates and potential risk factors in individuals with CF ages 6-20 at a single clinic in Washington state (N=85). Caries rates for enrolled CF participants and historical controls from NHANES were compared using cubic spline regression models. Generalized linear regression models identified correlates of age and caries in CF. Children ages 6-9 with CF had significantly lower caries than controls (Holm's P<0.05). There was no difference for ages 10-20 by CF status (Holm's P>0.05). Various biological/intraoral, medical, and behavioral factors were associated with caries and age in CF. Younger children with CF may be protected from caries, but there is apparent loss of protection in early adolescence associated with multiple risk factors. Additional studies are needed to confirm these findings.
JAMA Otolaryngology–Head & Neck Surgery, 2016
IMPORTANCE Sinusitis is the most common otolaryngologic complaint in children with cystic fibrosi... more IMPORTANCE Sinusitis is the most common otolaryngologic complaint in children with cystic fibrosis (CF). However, basic knowledge about the effect of sinusitis on these children is lacking. OBJECTIVE To evaluate the incidence and quality-of-life impact of chronic rhinosinusitis (CRS) in an unbiased cohort of children with CF. DESIGN, SETTING, AND PARTICIPANTS Survey study of consecutive pediatric patients with CF presenting for routine quarterly evaluation at a tertiary CF clinic at an academic pediatric hospital. Surveys were completed during the period from December 2012 to January 2013. MAIN OUTCOMES AND MEASURES Surveys designed to assess major criteria for diagnosis of CRS and a validated pediatric sinonasal quality-of-life instrument, the Sinonasal-5 (SN-5). Statistical analysis was performed to evaluate association between demographic features and survey responses. RESULTS Of the 102 consecutive eligible patients, 47 children (46%) aged 2 to 20 years (mean [SD] age, 12.9 [5.6] years; 24 [51%] female) completed the surveys. Depending on the exact diagnostic criteria used, 5 (11%) to 18 (38%) of children with CF had CRS. Mean domain (2.16; 95% CI, 2.02-2.30) and overall visual-analog scale (8.26; 95% CI, 8.01-8.51) scores on the SN-5 were consistent with minimal effect on quality of life and comparable to historical posttreatment scores. Mean scores on nasal obstruction (3.07; 95% CI, 2.80-3.34) and sinusitis (2.68;; 95% CI, 2.42-2.94) were the most affected domains, whereas allergy (1.83; 95% CI, 1.65-2.01), emotional disturbance (1.76; 95% CI, 1.56-1.96), and activity restriction (1.43; 95% CI, 1.31-1.57) were minimally affected. Children with a diagnosis of CRS had higher mean SN-5 scores (2.60; 95% CI, 2.31-2.89 vs 2.05; 95% CI, 1.90-2.20; difference of 0.55; 95% CI, 0.29-0.80). Twenty-five patients (53%) had undergone some treatment for sinusitis. There was no association between SN-5 score and CRS treatment history. CONCLUSIONS AND RELEVANCE In this study, the incidence of symptomatic CRS was high, but quality-of-life impact was relatively low among children with CF. Use of standardized assessment scales, including consensus diagnostic criteria and validated quality-of-life surveys, may be helpful to guide referral and management decisions.
Clinical Pharmacology and Therapeutics, 1994
I)isposition of drugs in cystic hbrosis. VI. In vivo activitv of cvtochrome P450 isoforms involve... more I)isposition of drugs in cystic hbrosis. VI. In vivo activitv of cvtochrome P450 isoforms involved i n thi metabolism of (R)-warfarin (including P450 3A4) is not enhanced in cystic fibrosis Objective: To determine whether the activity of cytochrome P450 isoforms involved in the metabolism of @)-warfarin is enhanced in cystic fibrosis. Design: Six adult subjects with cystic fibrosis and six healthy control subjects, matched by age and sex, were administered @)-warfarin as a single intravenous bolus dose (0.375 mglkg), and urine and plasma samples were collected for 192 hours. The concentration of @-warfarin in plasma and the concentration of @)-warfarin and its metabolites in urine were determined by HPLC and GCIMS, respectively. Plasma protein binding of @)-warfarin was measured by ultrafiltration. Results: The unbound plasma clearance of @)-warfarin was not significantly (p > 0.05) different between the cystic fibrosis and the control groups (cystic fibrosis, 997 + 483 mYhr/kg; control, 788 +-219 &/kg). The unbound metabolic clearances of @)-warfarin to its oxidative metabolites-6-h~droxywarfarin, 7-hydroxywarfarin, 8-hydroxywarfarin, and 10-hydroxywarfarin (mediated by P450 3A4)-were also similar @ > 0.05) in the two groups (6-hydrqwafarin: cystic fibrosis: 124.2 + 72.8 ml/hr/kg, control: 99.4 + 37.3 &/kg; 7-hydraxywafarin: cystic fibrosis: 43.8 + 32.2 &/kg, control: 34.5 + 10.6 &/kg; 8-hydrqwafarin: cystic fibrosis: 80.4 + 85.4 &/kg, control: 69.5 +. 39.5 &/kg; 10-hydraxywafarin: cystic fibrosis: 4.38 2 2.72 &/kg, control: 16.28 + 13.71 &r/kg). C m l~i o n : The in vivo activity of cytochrome P450 isoforms involved in the metabolism of @)-warfarin, including P450 3A4, is not enhanced in cystic fibrosis.
Proceedings of the National Academy of Sciences, 2006
Opportunistic infections are often polymicrobial. Two of the most important bacterial opportunist... more Opportunistic infections are often polymicrobial. Two of the most important bacterial opportunistic pathogens of humans, Pseudomonas aeruginosa and Staphylococcus aureus , frequently are coisolated from infections of catheters, endotracheal tubes, skin, eyes, and the respiratory tract, including the airways of people with cystic fibrosis (CF). Here, we show that suppression of S. aureus respiration by a P. aeruginosa exoproduct, 4-hydroxy-2-heptylquinoline- N -oxide (HQNO), protects S. aureus during coculture from killing by commonly used aminoglycoside antibiotics such as tobramycin. Furthermore, prolonged growth of S. aureus with either P. aeruginosa or with physiological concentrations of pure HQNO selects for typical S. aureus small-colony variants (SCVs), well known for stable aminoglycoside resistance and persistence in chronic infections, including those found in CF. We detected HQNO in the sputum of CF patients infected with P. aeruginosa , but not in uninfected patients, su...
Physiological Genomics, 2010
Airway inflammation and pulmonary disease are heterogeneous phenotypes in cystic fibrosis (CF) pa... more Airway inflammation and pulmonary disease are heterogeneous phenotypes in cystic fibrosis (CF) patients, even among patients with the same cystic fibrosis transmembrane conductance regulator (CFTR) genotype. Endothelin, a proinflammatory peptide and smooth muscle agonist, is increased in CF airways, potentially contributing to the pulmonary phenotype. Four cohorts of CF patients were screened for variants in endothelin pathway genes to determine whether any of these variants associated with pulmonary function. An initial cohort of 808 CF patients homozygous for the common CF mutation, ΔF508, showed significant association for polymorphisms in the endothelin receptor A gene, EDNRA ( P = 0.04), but not in the related endothelin genes ( EDN1, EDN2, EDN3, or EDNRB) or NOS1, NOS2A, or NOS3. Variants within EDNRA were examined in three additional cohorts of CF patients, 238 patients from Seattle, WA, 303 from Ireland and the U.K., and 228 from Cleveland, OH, for a total of 1,577 CF patien...
Pediatric Pulmonology, 2011
Pediatric Pulmonology, 2010
B. had full access to all of the data in the study and take full responsibility for the integrity... more B. had full access to all of the data in the study and take full responsibility for the integrity of all of the data and the accuracy of the data analysis, including all adverse effects.
Pediatric Pulmonology, 1999
The objective of this study was to assess the diagnostic accuracy of oropharyngeal (OP) cultures ... more The objective of this study was to assess the diagnostic accuracy of oropharyngeal (OP) cultures relative to simultaneous bronchoalveolar lavage (BAL) cultures in very young children with CF, and to examine the effects of bacterial density, age, and study cohort on diagnostic accuracy. Respiratory culture data were analyzed from three independent, prospective studies involving simultaneous collection of 286 OP and BAL cultures from 141 children with CF <5 years of age. For predicting any growth of Pseudomonas aeruginosa (Pa) from the lower airway in subjects Յ18 months of age (mean age, 8 ± 5 months), OP cultures had a sensitivity of 44% (95% CI 14%, 79%), specificity of 95% (90%, 99%), positive predictive value of 44% (14%, 79%), and negative predictive value of 95% (90%, 99%). Diagnostic accuracy was similar for Haemophilus influenzae (Hi). Specificity was significantly lower for Staphylococcus aureus (Sa). Sensitivity for all organisms improved if a positive lower airway culture was defined as Ն10 3 or Ն10 5 cfu/mL. Specificity for Pa declined significantly with increasing age. In children with CF <5 years of age, the specificity and negative predictive value of OP cultures for Pa are high, while the sensitivity and positive predictive value are poor. Thus, in this age range, a negative throat culture is helpful in "ruling out" lower airway infection with Pa. However, a positive culture does not reliably "rule in" the presence of Pa in the lower respiratory tract. These findings may have implications for study design and interpretation as well as clinical management of young children with CF.
Pediatric Pulmonology, 2007
Rationale: Among young children with cystic fibrosis (CF), Pseudomonas aeruginosa (Pa) airway inf... more Rationale: Among young children with cystic fibrosis (CF), Pseudomonas aeruginosa (Pa) airway infection is associated with increased morbidity and mortality. Early intervention strategies include tobramycin solution for inhalation (TSI), which can eradicate lower airway Pa from cultures obtained at the end of 28 days of treatment in young children. Methods: We conducted an open label, sequential cohort study of TSI in young children with CF to investigate duration of antimicrobial treatment effect. The primary outcome was lower airway Pa eradication per bronchoalveolar lavage (BAL) fluid culture. Sequential treatment cohorts varied by duration of treatment (28 or 56 days) and timing of follow-up BAL (at Days 56, 84, or 112). Subjects (N ¼ 36) were treated with TSI, 300 mg twice daily, for 28 days or 56 days per cohort assignment. Results: Among 31 evaluable subjects, culture based, lower airway Pa eradication was observed in the majority of subjects for up to 1-3 months following TSI treatment: 75% in Cohort 28/56 (days of treatment/day of follow-up BAL), 63% in Cohort 28/84, 82% in Cohort 56/112, and 75% in Cohort 28/112. Non-mucoid Pa at baseline and/or exotoxin A seronegativity were associated with higher rates of eradication. There was a less pronounced effect of TSI treatment on Pa eradication from oropharyngeal cultures in all cohorts. TSI treatment was associated with reduced neutrophilic airway inflammation and was not related to any serious adverse events. Conclusion: TSI monotherapy is safe and can eradicate lower airway Pa for up to 3 months after treatment in young children with CF.
The Journal of Pediatrics, 2009
Objectives-To assess the effects of Pseudomonas aeruginosa (Pa) and Staphylococcus aureus (Sa) in... more Objectives-To assess the effects of Pseudomonas aeruginosa (Pa) and Staphylococcus aureus (Sa) infection on lower airway inflammation and clinical status in young children with cystic fibrosis (CF). Study design-We studied 111 children < 6 years of age who had two Pa positive oropharyngeal cultures within 12 months. We examined bronchoalveolar lavage fluid (BALF) inflammatory markers (cell count, differential, IL-8, IL-6, neutrophil elastase), CF-related bacterial pathogens, exotoxin A serology, and clinical indicators of disease severity. Results-Young children with CF with both upper and lower airway Pa infection had higher neutrophil counts, IL-8 and free neutrophil elastase levels, increased likelihood of positive exotoxin A titers, and lower Shwachman scores compared with those with positive upper airway cultures only. Sa was associated with increased lower airway inflammation and the presence of both Pa and Sa had an additive effect on concentrations of lower airway inflammatory markers. BALF markers of inflammation increased with numbers of different bacterial pathogens detected. Conclusions-Young children with CF with upper and lower airway Pa infection have heightened endobronchial inflammation and poorer clinical status compared with children with only upper airway Pa infection. The independent and additive effects of Sa on inflammation support the importance of polymicrobial infection in early CF lung disease.
The Journal of Pediatrics, 2001
The Journal of Infectious Diseases, 2001
Pseudomonas aeruginosa lung infection is an important cause of morbidity and mortality in cystic ... more Pseudomonas aeruginosa lung infection is an important cause of morbidity and mortality in cystic fibrosis (CF). Longitudinal assessment of the phenotypic changes in P. aeruginosa isolated from young children with CF is lacking. This study investigated genotypic and phenotypic changes in P. aeruginosa from oropharynx (OP) and bronchoalveolar lavage fluid (BALF) in a cohort of 40 CF patients during the first 3 years of life; antibody response was also examined. A high degree of genotypic variability was identified, and each patient had unique genotypes. Early isolates had a phenotype distinct from those of usual CF isolates: generally nonmucoid and antibiotic susceptible. Genotype and phenotype correlated between OP and BALF isolates. As determined by culture, 72.5% of patients demonstrated P. aeruginosa during their first 3 years. On the basis of combined culture and serologic results, 97.5% of patients had evidence of infection by age 3 years, which suggests that P. aeruginosa infection occurs early in CF and may be intermittent or undetectable by culture.
Journal of Cystic Fibrosis, 2012
Background: Risk factors for initial Pseudomonas aeruginosa (Pa) acquisition, particularly enviro... more Background: Risk factors for initial Pseudomonas aeruginosa (Pa) acquisition, particularly environmental exposures, are poorly understood. We aimed to identify such risk factors in order to inform prevention strategies and identify high-risk populations. Methods: The study cohort included all participants in the U.S. EPIC Observational Study who had no prior Pa-positive respiratory cultures (N = 889). Cox proportional hazard models were used to test the effects of factors on age at first Pa-positive respiratory culture. Results: Cystic fibrosis (CF) genotype functional class had an important effect on age at initial Pa acquisition (hazard ratio (HR) comparing minimal to residual CFTR function 2.87 (95% CI 1.88, 4.39)). None of the modifiable risk factors evaluated, including cigarette smoke, hot tub use, breastfeeding, or daycare, was associated with age at Pa acquisition. Similarly, newborn screening was not associated with age at Pa acquisition (HR 0.85, 95% CI 0.66, 1.09). Key associations were validated in a CF Foundation National Patient Registry replication cohort. Conclusions: Given the ubiquitous presence of Pa in the environment, it may be that many imposed lifestyle changes will have less impact on age at initial Pa acquisition than genetic determinants.
Journal of Cystic Fibrosis, 2012
Background: Evaluation of physical activity is integral to the assessment of daily physical funct... more Background: Evaluation of physical activity is integral to the assessment of daily physical function and a potential objective outcome measure for clinical trials. We evaluated the feasibility of using pedometers to measure physical activity in adolescents and adults with cystic fibrosis (CF) and assessed the responsiveness of its measurement to changes in health state. Methods: Participants were recruited through two CF clinics in Seattle, WA. Subjects were instructed to use their pedometer for at least one ill and two well periods (each lasting 7 days). Step rate was calculated as steps per hour of use. Daily symptoms were also recorded using the CF Respiratory Symptom Diary (CFRSD). Generalized estimating equation linear regression was used to compare mean step rate between health states and by self-reported symptom category. Results: We enrolled 30 CF patients with a mean (±SD) age of 22 (±7) years and a mean forced expiratory volume in 1 s (FEV 1) of 57% (± 25%) predicted. The mean period step rate increased from 397 (95% CI 324-497) steps/hour when ill to 534 (95% CI 413-654) steps/hour when well (p = 0.015). Pedometer-recorded step rate also correlated with self-reported physical activity items on the CFRSD. Conclusion: Step rate measured with a pedometer correlates significantly with changes in health status and self-reported activity, and could be used as an outcome measure in CF.
JAMA, 2012
and Gilead. He has also served on a speakers board for Genentech and had meeting expenses paid by... more and Gilead. He has also served on a speakers board for Genentech and had meeting expenses paid by Pari. Mr. Rowbotham reports no financial disclosures. Ms. McNamara reports no financial disclosures. Ms. Johnson serves as a consultant for nSpire Health.
Clinical Infectious Diseases, 2013
Cystic fibrosis gastrointestinal disease includes nutrient malabsorption and intestinal inflammat... more Cystic fibrosis gastrointestinal disease includes nutrient malabsorption and intestinal inflammation. We show that the abundances of Escherichia coli in fecal microbiota were significantly higher in young children with cystic fibrosis than in controls and correlated with fecal measures of nutrient malabsorption and inflammation, suggesting that E. coli could contribute to cystic fibrosis gastrointestinal dysfunction.
Chest, 2007
Background: We hypothesized that adding 5 days of prednisone to standard therapy for acute pulmon... more Background: We hypothesized that adding 5 days of prednisone to standard therapy for acute pulmonary exacerbations in patients with cystic fibrosis (CF) would result in a more rapid and greater increase in lung function. Methods: CF patients with an acute pulmonary exacerbation were randomized to receive oral placebo or prednisone, 2 mg/kg/d up to 60 mg, on days 1 to 5 in addition to standard therapy. Study evaluations on days 1 to 6, 14, and 42 included spirometry, glucose measurements, sputum analysis, and symptom scores. Results: Twelve subjects were randomized to each arm. The slope of FEV 1 between day 1 and day 6 did not differ between evaluable subjects in the prednisone vs placebo groups (52 mL/d vs 51 mL/d, respectively). Mean increase in FEV 1 percentage of predicted did not differ significantly between prednisone vs placebo groups (day 6 [mean ؎ SD], 12.2 ؎ 5.2% vs 8.1 ؎ 10.5%; day 14, 14.7 ؎ 8.8% vs 10.2 ؎ 11.2%, respectively). Sputum inflammatory markers and symptom scores decreased between day 1 and day 14, but mean values did not differ between groups. Glucosuria occurred in six prednisone subjects, two of whom had hyperglycemia develop. Conclusions: In this pilot study, addition of oral corticosteroids to standard CF pulmonary exacerbation therapy did not result in a statistically significant effect on lung function or sputum markers of inflammation. Based on a trend toward improvement in pulmonary function with prednisone therapy, we obtained information for power calculations for a definitive study: 250 randomized subjects are required to detect a four-percentage-point treatment effect in FEV 1 percentage of predicted at day 14 to discriminate between null and alternative hypotheses.
American Journal of Respiratory and Critical Care Medicine, 2003
Induced sputum has been used to study airway inflammation. We sought to determine whether markers... more Induced sputum has been used to study airway inflammation. We sought to determine whether markers of infection and inflammation in induced sputum were a useful and safe outcome measure in cystic fibrosis. We hypothesized that bacterial density and inflammatory content of induced sputum would decrease after antibiotic therapy. Induced sputum was assayed for bacterial density, cell count, and differential and inflammatory markers before and after treatment with intravenous antibiotics. Fifty-five of the 72 subjects enrolled (mean age Ϯ SD 18.2 Ϯ 7.9 years) completed the study. FEV 1 increased by an average 0.3 Ϯ 0.3 L (10.4 Ϯ 8.7% predicted FEV 1), p Ͻ 0.0001; density of Pseudomonas aeruginosa and Staphylococcus aureus decreased by 2.4 Ϯ 3.1 log 10 cfu/g (p Ͻ 0.0005) and 4.0 Ϯ 2.3 log 10 cfu/ml (p Ͻ 0.0001), respectively; neutrophil count decreased by 0.4 Ϯ 0.6 log 10 cells/ml (p Ͻ 0.0001), interleukin-8 concentration by 0.5 Ϯ 1.3 log 10 pg/ml (p Ͻ 0.05), and neutrophil elastase by 0.4 Ϯ 0.7 log 10 g/ml (p Ͻ 0.005). Seven of 127 (6%) sputum induction procedures showed a decrease in FEV 1 of 20% or more. We conclude that markers in induced sputum may be useful, noninvasive outcome measures to assess response to therapies in cystic fibrosis studies.
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Papers by Sharon McNamara