Anne M Fitzpatrick

Emory University, Atlanta, Georgia, United States

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Publications (73)404.19 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The mechanisms underlying glucocorticoid responsiveness are largely unknown. Although redox regulation of the glucocorticoid receptor (GR) has been reported, it has not been studied in asthmatic patients. We characterized systemic cysteine oxidation and its association with inflammatory and clinical features in healthy children and children with difficult-to-treat asthma. We hypothesized that cysteine oxidation would be associated with increased markers of oxidative stress and inflammation, increased features of asthma severity, decreased clinically defined glucocorticoid responsiveness, and impaired GR function. PBMCs were collected from healthy children (n = 16) and children with asthma (n = 118) aged 6 to 17 years. Children with difficult-to-treat asthma underwent glucocorticoid responsiveness testing with intramuscular triamcinolone. Cysteine, cystine, and inflammatory chemokines and reactive oxygen species generation were quantified, and expression and activity of the GR were assessed. Cysteine oxidation was present in children with difficult-to-treat asthma and accompanied by increased reactive oxygen species generation and increased CCL3 and CXCL1 mRNA expression. Children with the greatest extent of cysteine oxidation had more features of asthma severity, including poorer symptom control, greater medication use, and less glucocorticoid responsiveness despite inhaled glucocorticoid therapy. Cysteine oxidation also modified the GR protein by decreasing available sulfhydryl groups and decreasing nuclear GR expression and activity. A highly oxidized cysteine redox state promotes a posttranslational modification of the GR that might inhibit its function. Given that cysteine oxidation is prevalent in children with difficult-to-treat asthma, the cysteine redox state might represent a potential therapeutic target for restoration of glucocorticoid responsiveness in this population. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
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    ABSTRACT: S-nitrosoglutathione is an endogenous airway smooth muscle relaxant. Increased airway S-nitrosoglutathione breakdown occurs in some asthma patients. We asked whether patients with increased airway catabolism of this molecule had clinical features that distinguished them from other asthma patients. We measured S-nitrosoglutathione reductase expression and activity in bronchoscopy samples taken from 66 subjects in the Severe Asthma Research Program. We also analysed phenotype and genotype data taken from the program as a whole. Airway S-nitrosoglutathione reductase activity was increased in asthma patients (p = 0.032). However, only a subpopulation was affected and this subpopulation was not defined by a "severe asthma" diagnosis. Subjects with increased activity were younger, had higher IgE and an earlier onset of symptoms. Consistent with a link between S-nitrosoglutathione biochemistry and atopy: 1) interleukin 13 increased S-nitrosoglutathione reductase expression and 2) subjects with an S-nitrosoglutathione reductase single nucleotide polymorphism previously associated with asthma had higher IgE than those without this single nucleotide polymorphism. Expression was higher in airway epithelium than in smooth muscle and was increased in regions of the asthmatic lung with decreased airflow. An early-onset, allergic phenotype characterises the asthma population with increased S-nitrosoglutathione reductase activity.
    European Respiratory Journal 10/2014; DOI:10.1183/09031936.00042414 · 7.13 Impact Factor
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    ABSTRACT: Airway hyperresponsiveness (AHR) is classically found in asthma, and persistent AHR is associated with poor asthma control. Although airway smooth muscle (ASM) cells play a critical pathophysiologic role in AHR, the paracrine contributions of surrounding cells such as fibroblasts to the contractile phenotype of ASM cells have not been examined fully. This study addresses the hypothesis that nicotine promotes a contractile ASM cell phenotype by stimulating fibroblasts to increase nerve growth factor (NGF) secretion into the environment.
    PLoS ONE 10/2014; 9(10):e109602. DOI:10.1371/journal.pone.0109602 · 3.53 Impact Factor
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    ABSTRACT: Severe asthma in children is characterized by sustained symptoms despite treatment with high doses of inhaled corticosteroids or oral corticosteroids. Children with severe asthma may fall into 2 categories, difficult-to-treat asthma or severe therapy-resistant asthma. Difficult-to-treat asthma is defined as poor control due to an incorrect diagnosis or comorbidities, or poor adherence due to adverse psychological or environmental factors. In contrast, treatment resistant is defined as difficult asthma despite management of these factors. It is increasingly recognized that severe asthma is a highly heterogeneous disorder associated with a number of clinical and inflammatory phenotypes that have been described in children with severe asthma. Guideline-based drug therapy of severe childhood asthma is based primarily on extrapolated data from adult studies. The recommendation is that children with severe asthma be treated with higher-dose inhaled or oral corticosteroids combined with long-acting β-agonists and other add-on therapies, such as antileukotrienes and methylxanthines. It is important to identify and address the influences that make asthma difficult to control, including reviewing the diagnosis and removing causal or aggravating factors. Better definition of the phenotypes and better targeting of therapy based upon individual patient phenotypes is likely to improve asthma treatment in the future.
    10/2014; 2(5):489–500. DOI:10.1016/j.jaip.2014.06.022
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    ABSTRACT: Background Although exhaled breath condensate (EBC) pH has been identified as an “emerging” biomarker of interest for asthma clinical trials, the clinical determinants of EBC pH remain poorly understood. Other studies have associated acid reflux–induced respiratory symptoms, for example, cough, with transient acidification of EBC. Objective We sought to determine the clinical and physiologic correlates of EBC acidification in a highly characterized sample of children with poorly controlled asthma. We hypothesized that (1) children with asymptomatic gastroesophageal reflux determined by 24-hour esophageal pH monitoring would have a lower EBC pH than children without gastroesophageal reflux, (2) treatment with lansoprazole would alter EBC pH in those children, and (3) EBC acidification would be associated with increased asthma symptoms, poorer asthma control and quality of life, and increased formation of breath nitrogen oxides (NOx). Methods A total of 110 children, age range 6 to 17 years, with poor asthma control and esophageal pH data enrolled in the Study of Acid Reflux in Children with Asthma (NCT00442013) were included. Children submitted EBC samples for pH and NOx measurement at randomization and at study weeks 8, 16, and 24. Results Serial EBC pH measurements failed to distinguish asymptomatic gastroesophageal reflux and was not associated with breath NOx formation. EBC pH also did not discriminate asthma characteristics such as medication and health care utilization, pulmonary function, and asthma control and quality of life both at baseline and across the study period. Conclusion Despite the relative ease of EBC collection, EBC pH as a biomarker does not provide useful information of children with asthma who were enrolled in asthma clinical trials.
    09/2014; DOI:10.1016/j.jaip.2014.04.006
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    ABSTRACT: Background: Anti-microbial peptide, LL-37, is produced in response to active vitamin D to exert immunomodulatory effects and inhibits HIV replication in vitro. To date, no studies have investigated LL-37 in HIV-infected patients. This study sought to investigate LL-37 and the relationship to 25-hydroxyvitamin D (25(OH)D) and HIV-related variables in this population. Methods: HIV-infected subjects and healthy controls ages 1-25 years old were prospectively enrolled in this cross-sectional study. Fasting plasma LL-37 and 25(OH)D concentrations were measured in duplicate with ELISA. Results: HIV+ subjects (36 antiretroviral therapy (ART)-experienced; 27 ART-naïve) and 31 healthy controls were enrolled. Overall, 93% were black and median age was 20 years. There was no difference in median (interquartile range) LL-37 between the HIV-infected group and controls (58.3 (46.4,69.5) vs. 51.3 (40.8,98.2) µg/mL, respectively; P=0.57); however, ART-experienced had higher concentrations than ART-naïve (66.2 (55.4,77.0) vs. 48.9 (38.9,57.9) µg/mL, respectively; P<0.001). LL-37 was positively correlated with 25(OH)D in controls, but not in HIV-infected groups, and was positively correlated with current CD4 and ∆CD4 (current-nadir) in ART-experienced. After adjustment for age, race, sex, and HIV duration, the association between LL-37 and CD4 remained significant. Conclusions: LL-37 was associated with 25(OH)D in healthy controls but not in HIV-infected subjects. LL-37 concentrations were higher in ART-experienced compared to ART-naïve, and were associated with CD4 counts and immune restoration after treatment. These findings suggest that HIV and/or HIV-related variables may alter the expected positive relationship between vitamin D and LL-37 and should be further investigated.
    AIDS research and human retroviruses 05/2014; 30(7). DOI:10.1089/AID.2013.0279 · 2.46 Impact Factor
  • Article: Reply.
    The Journal of allergy and clinical immunology 04/2014; DOI:10.1016/j.jaci.2014.03.013 · 11.25 Impact Factor
  • Article: Reply.
    Anne M Fitzpatrick, Youngja Park, Lou Ann Brown, Dean P Jones
    The Journal of allergy and clinical immunology 03/2014; DOI:10.1016/j.jaci.2014.02.012 · 11.25 Impact Factor
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    ABSTRACT: AsthmaSESSION TYPE: Slide PresentationsPRESENTED ON: Saturday, March 22, 2014 at 12:15 PM - 01:15 PMPURPOSE: The progression and development of asthma across the menopausal transition has not been thoroughly addressed, or clearly separated from the effects of age. The present study evaluates the effects of menopause on asthma severity, quality of life and healthcare utilization using a propensity score model. The analyses were conducted using data from participants enrolled in the Severe Asthma Research program (SARP). Ten sites enrolled asthmatics between 2002 to 2011, and contributed a standardized set of data to a central coordinating center [AJRCCM 2012;185:356-62]. Data on 166 menopausal and 538 non-menopausal asthmatic women, older than 18 years of age was available for analyses. The effect of menopause on asthma control, asthma quality of life, and all secondary endpoints was analyzed after conducting a Propensity Score matching with subsequent multivariate analysis using conditional logistic regression to adjust for the effect of the covariates that remained unbalanced after matching. Those unbalanced covariates were: the age at enrollment, gastroesophageal reflux disease, and hypertension. Compared to non-menopaused women, menopaused women were older, reported more gastroesophageal reflux disease, sinusitis history and used more inhaled corticosteroids. They were less likely to have atopy or test positively on skin testing. Unadjusted analysis showed that menopaused women had an odds ratio of 5.62(95 CI: 3.83; 8.26) of severe asthma compared to non-menopaused women. They were more likely to require healthcare utilization. After Propensity Score matching with subsequent multivariate adjustment menopause was neither associated with greater incidence of severe asthma [OR:1.75 (95 CI: 0.52; 5.9)], or with a worse asthma quality of life [mean difference: 0.31 (95 CI: -0.30; 0.93)]. The increased unadjusted asthma severity, increased need for treatment and health care utilization in menopaused women are more likely due to other age associated co-morbidities and/or aging dependent conditions. In elderly women, menopause is unlikely to be the reason for increased risk of severe asthma or worse quality of life. Suzy Comhair: Grant monies (from sources other than industry): NIH (HL69170) The following authors have nothing to disclose: Joe Zein, Eugene Bleecker, William Busse, William Calhoun, Mario Castro, K. Fan Chung, Raed Dweik, Anne Fitzpatrick, Benjamin Gaston, Elliot Israel, Nizar Jarjour, Wendy Moore, Gerald Teague, Sally Wenzel, Serpil ErzurumNo Product/Research Disclosure Information.
    Chest 03/2014; 145(3 Suppl):22A. DOI:10.1378/chest.1783148 · 7.13 Impact Factor
  • Anne M Fitzpatrick, Youngja Park, Lou Ann S Brown, Dean P Jones
    The Journal of allergy and clinical immunology 01/2014; 133(1):258-261.e8. DOI:10.1016/j.jaci.2013.10.012 · 11.25 Impact Factor
  • 12/2013; 10(Supplement):S118-S124. DOI:10.1513/AnnalsATS.201309-307AW
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    ABSTRACT: The Eunice Kennedy Shriver National Institute of Child Health and Human Development convened an Asthma Group in response to the Best Pharmaceuticals for Children Act. The overall goal of the Best Pharmaceuticals for Children Act Program is to improve pediatric therapeutics through preclinical and clinical drug trials that lead to drug-labeling changes. Although significant advances have been made in the understanding and management of asthma in adults with appropriately labeled medications, less information is available on the management of asthma in children. Indeed, many medications are inadequately labeled for use in children. In general, the younger the child, the less information there is available to guide clinicians. Because asthma often begins in early childhood, it is incumbent on us to continue to address the primary questions raised in this review and carefully evaluate the medications used to manage asthma in children. Meanwhile, continued efforts should be made in defining effective strategies that reduce the risk of exacerbations. If the areas of defined need are addressed in the coming years, namely prevention of exacerbations and progression of disease, as well as primary intervention, we will see continuing reduction in asthma mortality and morbidity along with improved quality of life for children with asthma.
    The Journal of allergy and clinical immunology 11/2013; 133(1). DOI:10.1016/j.jaci.2013.10.018 · 11.25 Impact Factor
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    ABSTRACT: Childhood asthma clusters, or subclasses, have been developed by computational methods without evaluation of clinical utility. To replicate and determine whether childhood asthma clusters previously identified computationally in the Severe Asthma Research Program (SARP) are associated with treatment responses in Childhood Asthma Research and Education (CARE) Network clinical trials. A cluster assignment model was determined by using SARP participant data. A total of 611 participants 6 to 18 years old from 3 CARE trials were assigned to SARP pediatric clusters. Primary and secondary outcomes were analyzed by cluster in each trial. CARE participants were assigned to SARP clusters with high accuracy. Baseline characteristics were similar between SARP and CARE children of the same cluster. Treatment response in CARE trials was generally similar across clusters. However, with the caveat of a smaller sample size, children in the early-onset/severe-lung function cluster had best response with fluticasone/salmeterol (64% vs 23% 2.5× fluticasone and 13% fluticasone/montelukast in the Best ADd-on Therapy Giving Effective Responses trial; P = .011) and children in the early-onset/comorbidity cluster had the least clinical efficacy to treatments (eg, -0.076% change in FEV1 in the Characterizing Response to Leukotriene Receptor Antagonist and Inhaled Corticosteroid trial). In this study, we replicated SARP pediatric asthma clusters by using a separate, large clinical trials network. Early-onset/severe-lung function and early-onset/comorbidity clusters were associated with differential and limited response to therapy, respectively. Further prospective study of therapeutic response by cluster could provide new insights into childhood asthma treatment.
    The Journal of allergy and clinical immunology 10/2013; 133(2). DOI:10.1016/j.jaci.2013.09.002 · 11.25 Impact Factor
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    ABSTRACT: Food allergy affects 8% of preschool children, but factors responsible for food allergy in children are poorly understood. Use of antacid medication may be a contributing factor. The purpose of this study was to determine if parent-reported antacid medication use was associated with higher prevalence of food allergy in atopic children. In this cross-sectional study, parents of children with atopic diseases completed a questionnaire relating to a history of treatment with antacid medication and food allergy. Charts were independently reviewed for food-specific IgE and/or skin-prick test results. Food allergy was defined as a reaction to a food consistent with the anaphylaxis consensus statement and either an elevated food-specific IgE or a positive food skin-prick test. One hundred four questionnaires were completed. Mean age of the participating children was 7.0 ± 4.3 years (range, 5 months to 18 years of age). Forty-seven (45%) individuals were reported to have taken an antacid medication in the past. History of taking antacid medication was associated with an increased prevalence (57% (27)/47 versus 32% (18)/57) and higher prevalence of food allergy of having food allergy (aPR, 1.7 [1.1-2.5]). Mean peanut food-specific IgE was higher in those with a history of taking antacid medication (11.0 ± 5.0 versus 2.0 ± 5.5.; p = 0.01). History of treatment with antacid medication is associated with an increased prevalence of having food allergy.
    Allergy and Asthma Proceedings 05/2013; 34(3):227-32. DOI:10.2500/aap.2013.34.3657 · 3.35 Impact Factor
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    ABSTRACT: Diesel exhaust particle (DEP) exposure enhances allergic inflammation and has been linked to the incidence of asthma. Oxidative stress on the thiol molecules cysteine (Cys) and glutathione (GSH) can promote inflammatory host responses. The effect of DEP on the thiol oxidation/reduction (redox) state in the asthmatic lung is unknown. To determine if DEP exposure alters the Cys or GSH redox state in the asthmatic airway. Bronchoalveolar lavage fluid was obtained from a house dust mite (HDM) induced murine asthma model exposed to DEP. GSH, glutathione disulfide (GSSG), Cys, cystine (CySS), and s-glutathionylated cysteine (CySSG) were determined by high pressure liquid chromatography. DEP co-administered with HDM, but not DEP or HDM alone, decreased total Cys, increased CySS, and increased CySSG without significantly altering GSH or GSSG. DEP exposure promotes oxidation and S-glutathionylation of cysteine amino acids in the asthmatic airway, suggesting a novel mechanism by which DEP may enhance allergic inflammatory responses.
    PLoS ONE 03/2013; 8(3):e60632. DOI:10.1371/journal.pone.0060632 · 3.53 Impact Factor
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    ABSTRACT: Although studies in adults have shown a non-TH2 obese asthma phenotype, whether a similar phenotype exists in children is unclear. We hypothesized that asthmatic children with obesity, defined as a body mass index above the 95th percentile for age and sex, would have poorer asthma control as well as decreased quality of life, increased health care utilization, and decreased pulmonary function measures as a function of increased TH1 versus TH2 polarization. This study involved a post hoc analysis of cross-sectional data from 269 children 6 to 17 years of age enrolled in the National Heart, Lung, and Blood Institute Severe Asthma Research Program. Children answered questionnaires and underwent spirometry, plethysmography, exhaled nitric oxide determination, and venipuncture for TH1/TH2 cytokine determination. Asthma control was defined according to national asthma treatment guidelines that are based on prespecified thresholds for lung function and symptom frequency. Fifty-eight children (22%) were overweight and 67 (25%) were obese. Obese children did not have poorer asthma control but were more likely to report nonspecific symptoms such as dyspnea and nocturnal awakenings. Obese children did have decreased asthma-related quality of life and increased health care utilization, but this was not associated with airflow limitation. Instead, obese children had decreased functional residual capacity. A unique pattern of TH1 or TH2 polarization was not observed. Poor asthma control in obese children with asthma may be overestimated because of enhanced perception of nonspecific symptoms such as dyspnea that results from altered mechanical properties of the chest wall. Careful assessment of physiologic as well as symptom-based measures is needed in the evaluation of obese children with respiratory symptoms.
    01/2013; 1(1):39-45.e2. DOI:10.1016/j.jaip.2012.10.006
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    ABSTRACT: Introduction: Increasing BMI has been associated with less fractional exhaled nitric oxide. This may be explained by an increase in the concentration of asymmetric di-methyl arginine (ADMA) relative to L-arginine, which can lead to greater nitric oxide synthase uncoupling. This mechanism may differ across age of asthma onset and predict asthma morbidity. METHODS: Cross sectional study of participants from the Severe Asthma Research Program (SARP), across early (<12 yrs.) and late (> 12 yrs.) onset asthma phenotypes RESULTS: Late onset asthmatics had a higher median plasma ADMA level (0 .48 μM [IQR 0.35 - 0.7] compared to early onset: (0.37 μM [IQR 0.29 - 0.59], p=0.01), and lower median plasma L-arginine (late onset 52.3 [IQR 43 - 61]) compared to 51 μM [IQR 39 - 66] (early onset); p=0.02). The log of plasma L-arginine/ADMA was inversely correlated with BMI in the late (r = -0.4, p=0.0006) in contrast to the early onset phenotype (r = -0.2, p=0.07). Although FeNO was inversely associated with BMI in the late onset phenotype (p=0.02), the relationship was lost after adjusting for L-arginine/ADMA. Also in this phenotype, a reduced L-arginine/ADMA was associated with less IgE, increased respiratory symptoms, lower lung volumes, and worse asthma quality of life. CONCLUSIONS: In late onset asthma phenotype, plasma ratios of L-arginine to ADMA may explain the inverse relationship of BMI to FeNO. In addition, these lower L-arginine/ADMA ratios are associated with reduced lung function, and increased respiratory symptoms frequency, suggesting a role in the pathobiology of the late onset phenotype.
    American Journal of Respiratory and Critical Care Medicine 11/2012; 187(2). DOI:10.1164/rccm.201207-1270OC · 11.99 Impact Factor
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    ABSTRACT: Objective:Alterations in inflammatory mediators are an important finding in neonates who develop bronchopulmonary dysplasia (BPD); however, there is a lack of research examining the relationship between multiple inflammatory mediators in premature neonates and the development of BPD. This study investigated whether the distribution of 12 inflammatory mediators detected in the tracheal aspirate (TA) of neonates within 24 h of birth could differentiate between neonates who did and who did not develop BPD.Study design:TA samples were collected from 27 very low birth weight neonates (BPD+=11), and the concentrations of 12 biomarkers associated with BPD were determined. Linear discriminant analysis (LDA) was used to classify neonates into two outcome groups.Result:LDA based on the 12 measured biomarkers displayed a significant level of discriminant function (P=0.007).Conclusion:Using linear discriminant analysis, predictive models of BPD can be generated. Our results suggest that multiple inflammatory mediators collected within 24 h of birth may be used to classify neonates into who will and who will not develop BPD.Journal of Perinatology advance online publication, 4 October 2012; doi:10.1038/jp.2012.125.
    Journal of perinatology: official journal of the California Perinatal Association 10/2012; 33(5). DOI:10.1038/jp.2012.125 · 2.35 Impact Factor
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    ABSTRACT: Vitamin D deficiency is common in HIV-infected individuals. In adults, traditional and HIV-related factors play a role in vitamin D status, and deficiency appears to impair immune restoration and exacerbate HIV complications, like cardiovascular disease (CVD). This study sought to determine factors contributing to vitamin D status in HIV-infected youth and investigate the relationship with CVD risk, inflammation and immune restoration. HIV-infected subjects (1-25 years old) were enrolled prospectively along with healthy controls that were group-matched by age, sex and race. HIV data were collected for the HIV-infected group, while traditional risk factors, including vitamin D intake, sun exposure, skin pigmentation, physical activity level and body mass index (BMI) were collected for both groups. Fasting lipids, plasma 25-hydroxyvitamin D (25[OH]D), and inflammation markers were measured. In total, 200 HIV-infected subjects and 50 controls were enrolled. HIV group had 53% male, 95% Black and a mean age of 17.2 ±4.6 years. There was no difference in 25(OH)D between groups; 77% of HIV+ and 74% of controls had 25(OH)D<20 ng/ml. Only Fitzpatrick skin type was independently associated with 25(OH)D. No HIV variables were associated with 25(OH)D, even when HIV sub-populations were examined. Inflammation, CVD risk factors and immune restoration were not independently associated with 25(OH)D. Vitamin D deficiency is common among HIV-infected youth. However, HIV factors, CVD risk, inflammation and immune restoration do not appear to have the same relationship with vitamin D as has been shown in adults. Supplementation trials are needed to determine if increasing 25(OH)D concentrations could better elucidate these relationships.
    Antiviral therapy 08/2012; 17(6):1069-78. DOI:10.3851/IMP2318 · 3.14 Impact Factor