Geoffrey L Chupp

Yale-New Haven Hospital, New Haven, Connecticut, United States

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Publications (39)370.64 Total impact

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    ABSTRACT: The airway transcriptome includes genes that contribute to the pathophysiologic heterogeneity seen in individuals with asthma. We analyzed sputum gene expression for transcriptomic endotypes of asthma (TEA); gene signatures that discriminate phenotypes of disease. Gene expression in sputum and blood of asthma patients was measured using Affymetrix gene expression microarrays. Unsupervised clustering analysis based on pathways from the Kyoto Encyclopedia of Genes and Genomes was used to identify TEA clusters. Logistic regression analysis of matched blood samples defined an expression profile in the circulation to determine the TEA cluster assignment in a cohort of children with asthma for validation. Three TEA clusters were identified. TEA cluster 1 had the most subjects with a history of intubation (P = 0.05), a lower pre-bronchodilator FEV1 (P = 0.006), a higher bronchodilator response (P = 0.03), and higher exhaled nitric oxide levels (P = 0.04), compared to the other TEA clusters. TEA cluster 2, the smallest cluster had the most subjects that were hospitalized for asthma (P = 0.04). TEA cluster 3, the largest cluster, had normal lung function, low exhaled nitric oxide levels, and lower inhaled steroid requirements. Evaluation of TEA clusters in children confirmed that TEA clusters 1 and 2 are associated with a history of intubation (P = 5.58 x 10-06) and hospitalization (P = 0.01), respectively. There are common patterns of gene expression in the sputum and blood of children and adults that are associated with near fatal, severe and milder asthma.
    American Journal of Respiratory and Critical Care Medicine 03/2015; 191(10). DOI:10.1164/rccm.201408-1440OC
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    ABSTRACT: Rationale: Obesity, especially truncal obesity, is a risk factor for asthma incidence, prevalence and severity. Chitinase 3-like-1 (Chi3l1) is an evolutionarily conserved moiety that plays a critical role in antipathogen and Th2 responses. However, the mechanisms that underlie the association between asthma and obesity and the role(s) of Chi3l1 in fat accumulation have not been defined. Objective: We hypothesized that that Chi3l1 is regulated by a high fat diet (HFD) and simultaneously plays an important role(s) in the pathogenesis of asthma and obesity. Methods: We evaluated the regulation of Chi3l1 by a HFD and Th2 inflammation. We also used genetically modified mice to define the roles of Chi3l1 in white adipose tissue (WAT) accumulation and Th2 inflammation and blockers of Sirtuin 1 (Sirt1) to define its roles in these responses. Lastly, the human-relevance of these findings was assessed with a case-control study involving obese and lean controls and asthmatics. Measurements and Results: These studies demonstrate that a HFD and aeroallergen challenge augment the expression of WAT and pulmonary Chi3l1. Chi3l1 also played a critical role in WAT accumulation and lung Th2 inflammation. In addition, Chi3l1 inhibited Sirt1 expression and the deficient visceral fat and Th2 responses in Chi3l1 null mice were reversed by Sirt1 inhibition. Lastly, serum and sputum Chi3l1 were positively associated with truncal adiposity and serum Chi3l1 was associated with persistent asthma and low lung function in obese asthmatics. Conclusion: Chi3l1 is induced by a HFD and Th2 inflammation and simultaneously contributes to the genesis of obesity and asthma.
    American Journal of Respiratory and Critical Care Medicine 01/2015; 191(7). DOI:10.1164/rccm.201405-0796OC
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    ABSTRACT: Single nucleotide polymorphisms (SNPs) in the chitinase 3-like 1 (CHI3L1) promoter, the gene encoding YKL-40, are associated with circulating YKL-40 levels and asthma prevalence. However, the effects of gene polymorphisms on asthma severity and airway expression of YKL-40 have not been examined. We sought to determine the effect of genetic variation in CHI3L1 on asthma severity and YKL-40 expression in subjects from the Yale Center for Asthma and Airways Disease and the Severe Asthma Research Program. SNPs spanning the CHI3L1 gene were genotyped in 259 Yale Center for Asthma and Airways Disease and 919 Severe Asthma Research Program subjects. Association and haplotype analyses were conducted to identify effects on airflow obstruction, YKL-40 levels, and asthma severity. Fifteen SNPs in CHI3L1 were associated with FEV1, serum YKL-40 levels, or both. rs12141494 (intron 6) was the only SNP in subjects of European ancestry in both cohorts that was associated with serum YKL-40 levels and postbronchodilator FEV1. Conditional analysis demonstrated that the effect on lung function was independent of the promoter SNP rs4950928, and haplotype analysis demonstrated that G alleles at rs12141494 and rs4950928 are associated with lower YKL-40 expression and higher FEV1 percent predicted values. In asthmatic subjects the risk allele A at rs12141494 was associated with severe asthma and higher YKL-40 expression in the airway (P ≤ .05). In contrast to the promoter SNP rs4950928, the intronic SNP rs12141494 in CHI3L1 is associated with asthma severity, lung function, and YKL-40 expression in the blood and airway. These data suggest that SNP rs12141494 modulates YKL-40 expression in the airway and contributes to airway remodeling and asthma severity. Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
    Journal of Allergy and Clinical Immunology 01/2015; DOI:10.1016/j.jaci.2014.11.027
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    ABSTRACT: The aim of this study is to identify the predictors of hospital readmission or early unplanned return to clinic within 30 days of discharge after pulmonary lobectomy. The medical records of patients undergoing lobectomy by the thoracic surgery service between January 2009 and July 2012 were reviewed. All lobectomies were included irrespective of the etiology of disease. Multivariate logistic regression methods were used to identify predictors of readmission and or early unplanned return to clinic. Two hundred thirteen patients underwent a pulmonary lobectomy during the study period (median age, 67 years). Pathologic diagnosis was malignant in 94% of the patients and benign in 6%. Minimally invasive approaches were used in 69% of the patients, whereas open thoracotomy was used in 31%. Median hospital length of stay was 4 days, and postoperative mortality occurred in 1 patient (0.5%). The Charlson comorbidity index was 1 ± 1. Predicted postoperative forced expiratory volume in 1 second and diffusing capacity of the lung for carbon monoxide were 68% ± 18% and 64% ± 17%, respectively. Postoperative complications occurred in 31% of patients; 13% required readmission to the hospital within 30 days of discharge or early unplanned return to clinic. Predictors of readmission or early unplanned return to clinic were unplanned transfer to the intensive care unit (odds ratio, 10.4; 95% confidence interval, 1.1 to 103.5; p = 0.04) and Charlson comorbidity index greater than 0 (odds ratio, 1.5; 95% confidence interval, 1.04 to 2.03; p = 0.03). Readmission or early unplanned return to clinic was independent of surgical approach (p = 0.32). Patients who require a postoperative transfer to the intensive care unit or with higher Charlson comorbidity index are at higher risk for hospital readmission after pulmonary lobectomy. Readmission was not affected by the surgical approach. Whether a different strategy to follow-up for these high-risk patients can prevent readmission remains to be determined. Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.
    The Annals of Thoracic Surgery 12/2014; 99(2). DOI:10.1016/j.athoracsur.2014.10.014
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    ABSTRACT: Rationale: Cytokine receptors can be markers defining different T cell subsets and considered as therapeutic targets. The association of IL-6 and IL-6 receptor alpha (IL-6Rα) with asthma was reported, suggesting their involvement in asthma. Objectives: To determine whether and how IL-6Rα defines a distinct effector memory (EM) CD8+ T cell population in health and disease. Methods: EM CD8+ T cells expressing IL-6Rα (IL-6Rαhigh) were identified in human peripheral blood and analyzed for function, gene and transcription factor expression. The relationship of these cells with asthma was determined using blood and sputum. Measurements and Main results: A unique population of IL-6Rαhigh EM CD8+ T cells was found in peripheral blood. These cells that potently proliferated, survived, and produced high levels of the Th2-type cytokines IL-5 and IL-13 had increased levels of GATA3 and decreased levels of T-bet and Blimp-1 in comparison to other EM CD8+ T cells. In fact, GATA3 was required for IL-6Rα expression. Asthmatic patients had an increased frequency of IL-6Rαhigh EM CD8+ T cells in peripheral blood compared to healthy controls. Also, IL-6Rαhigh EM CD8+ T cells exclusively produced IL-5 and IL-13 in response to asthma-associated respiratory syncytial virus and bacterial superantigens. Conclusions: Human IL-6Rαhigh EM CD8+ T cells is a unique cell subset that may serve as a reservoir for effector CD8+ T cells, particularly the ones producing Th2-type cytokines, and expand in asthma.
    American Journal of Respiratory and Critical Care Medicine 11/2014;
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    ABSTRACT: Rationale: Cytokine receptors can be markers defining different T cell subsets and considered as therapeutic targets. The association of IL-6 and IL-6 receptor alpha (IL-6Rα) with asthma was reported, suggesting their involvement in asthma. Objectives: To determine whether and how IL-6Rα defines a distinct effector memory (EM) CD8+ T cell population in health and disease. Methods: EM CD8+ T cells expressing IL-6Rα (IL-6Rαhigh) were identified in human peripheral blood and analyzed for function, gene and transcription factor expression. The relationship of these cells with asthma was determined using blood and sputum. Measurements and Main results: A unique population of IL-6Rαhigh EM CD8+ T cells was found in peripheral blood. These cells that potently proliferated, survived, and produced high levels of the Th2-type cytokines IL-5 and IL-13 had increased levels of GATA3 and decreased levels of T-bet and Blimp-1 in comparison to other EM CD8+ T cells. In fact, GATA3 was required for IL-6Rα expression. Asthmatic patients had an increased frequency of IL-6Rαhigh EM CD8+ T cells in peripheral blood compared to healthy controls. Also, IL-6Rαhigh EM CD8+ T cells exclusively produced IL-5 and IL-13 in response to asthma-associated respiratory syncytial virus and bacterial superantigens. Conclusions: Human IL-6Rαhigh EM CD8+ T cells is a unique cell subset that may serve as a reservoir for effector CD8+ T cells, particularly the ones producing Th2-type cytokines, and expand in asthma.
    American Journal of Respiratory and Critical Care Medicine 11/2014; DOI:10.1164/rccm.201403-0601OC
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    ABSTRACT: Rationale: Growth arrest-specific gene 6 (Gas6) is a secreted vitamin K-dependent protein with pleiotropic effects via activation of receptor tyrosine kinase Tyro3, Axl, and Mertk receptors but little is known about its role in allergic airway disease. Objectives: We investigated the role of Gas6 in the development of fungal allergic airway disease in mice. Methods: The immune response was evaluated in Gas6 deficient (Gas6-/-) and wildtype (WT) mice, and in recombinant Gas6-treated WT mice during Aspergillus fumigatus-induced allergic airway disease. Measurements and Main Results: Gas6 plasma levels were significantly elevated in adult, clinical asthma of all severities compared with non-asthmatics. In a murine model of fungal allergic airway disease, increased protein expression of both Axl and Mertk were observed in the lung. Airway hyper-responsiveness (AHR), whole lung Th2 cytokine levels, goblet cell metaplasia, and peribronchial fibrosis were ameliorated in Gas6-/- mice compared with WT mice with fungal allergic airway disease. Intranasal Gas6 administration into WT mice had a divergent effect on airway inflammation and AHR. Specifically, a total dose of 2 μg of exogenous Gas6 (i.e. low dose) significantly increased whole lung Th2 cytokine levels and subsequent AHR, whereas a total dose of 7 μg of exogenous Gas6 (i.e. high dose) significantly suppressed both Th1 and Th2 cytokines and AHR compared with appropriate control groups. Mechanistically, Gas6 promoted Th2 activation via its highest affinity receptor Axl expressed by myeloid DCs. Intranasal administration of Gas6 consistently exacerbated airway remodeling compared with control WT groups. Conclusions: These results demonstrate that Gas6 enhances several features of fungal allergic airway disease.
    American Journal of Respiratory Cell and Molecular Biology 05/2014; DOI:10.1165/rcmb.2014-0049OC
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    ABSTRACT: Background:Observational studies suggest that asthma control improves after adenotonsillectomy, but longitudinal studies that correlate the effect of the procedure on the levels of biomarkers associated with airway inflammation are limited.Methods:We conducted a longitudinal, observational study on pediatric patients, both with and without asthma, undergoing adenotonsillectomy. Asthma control test (ACT) scores and chitinase activity in the circulation were measured at time of surgery and at 6-mo follow-up.Results:Sixty-six children with asthma and 64 control subjects were enrolled. Mean ACT scores improved by three points (P < 0.001) after 6 mo. 85% of children with poorly controlled asthma demonstrated an increase in ACT score of at least three points or a decrease in emergency department/urgent care visits, oral corticosteroid courses, or rescue short acting bronchodilator usage. Chitinase activity decreased significantly in asthmatics who improved (P < 0.01). Higher chitinase activity levels at baseline were associated with improved asthma control following surgery (P < 0.01).Conclusion:In children with high preoperative circulating chitinase activity levels, asthma control and healthcare utilization were significantly improved after adenotonsillecotmy. Chitinase activity decreased after surgery in children with improved control. This suggests that adenotonsillectomy modulates chitinase activity, affecting airway inflammation and improving airway disease.Pediatric Research (2014); doi:10.1038/pr.2013.237.
    Pediatric Research 12/2013; DOI:10.1038/pr.2013.237
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    ABSTRACT: BACKGROUND: Allergic airway inflammation contributes to the airway remodelling that has been linked to increased obstruction and morbidity in asthma. However, the mechanisms by which allergens contribute to airway remodelling in humans are not fully established. CCL18, chitotriosidase (CHIT1) and YKL-40 are readily detectable in the lungs and contribute to remodelling in other fibrotic diseases, but their involvement in allergic asthma is unclear. OBJECTIVE: We hypothesized that CCL18, YKL-40 and CHIT1 bioactivity are enhanced in allergic asthma subjects after segmental allergen challenge and are related to increased pro-fibrotic and Th2-associated mediators in the lungs. METHODS: Levels of CCL18 and YKL-40 protein and chitotriosidase (CHIT1) bioactivity in bronchoalveolar lavage (BAL) fluid, as well as CCL18, YKL-40 and CHIT1 mRNA levels in BAL cells were evaluated in patients with asthma at baseline and 48 h after segmental allergen challenge. We also examined the correlation between CCL18 and YKL-40 levels and CHIT1 activity with the levels of other pro-fibrotic factors and chemokines previously shown to be up-regulated after allergen challenge. RESULTS: Chitotriosidase activity and YKL-40 and CCL18 levels were elevated after segmental allergen challenge and these levels correlated with those of other pro-fibrotic factors, T cell chemokines, and inflammatory cells after allergen challenge. CCL18 and YKL-40 mRNA levels also increased in BAL cells after allergen challenge. CONCLUSIONS AND CLINICAL RELEVANCE: Our results suggest that CCL18 and YKL-40 levels and CHIT1 activity are enhanced in allergic airway inflammation and thus may contribute to airway remodelling in asthma.
    Clinical & Experimental Allergy 02/2013; 43(2):187-197. DOI:10.1111/cea.12032
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    ABSTRACT: Kidney hypoperfusion during episodes of systemic hypotension or after surgical procurement for transplantation can lead to tubular cell death via necrosis and apoptosis, which trigger a series of responses that promote repair. The factors that contribute to the repair phase after kidney injury are not well understood. Using a urine proteomic screen in mice, we identified the macrophage-secreted chitinase-like protein Brp-39, the murine protein product of the chitinase 3-like 1 gene, as a critical component of this reparative response that serves to limit tubular cell apoptotic death via activation of Akt, improving animal survival after kidney ischemia/reperfusion. Examination of graded times of renal ischemia revealed a direct correlation between the degree of kidney injury and both Chi3l1/Brp-39 expression in the kidney and its levels in the urine. In samples collected from patients undergoing deceased-donor kidney transplantation, we found higher levels of the orthologous human protein, YKL-40, in urine and blood from allografts subjected to sufficient peri-transplant ischemia to cause delayed graft function than from allografts with slow or immediate graft function. Urinary levels of YKL-40 obtained within hours of transplant predicted the need for subsequent dialysis in these patients. In summary, these data suggest that Brp-39/YKL-40 is a sensor of the degree of injury, a critical mediator of the reparative response, and a possible biomarker to identify patients at greatest risk of sustained renal failure after transplantation.
    Journal of the American Society of Nephrology 01/2013; 24(2). DOI:10.1681/ASN.2012060579
  • American Thoracic Society 2012 International Conference, May 18-23, 2012 • San Francisco, California; 05/2012
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    ABSTRACT: IL-33 and its soluble receptor and cell-associated receptor (ST2L) are all increased in clinical and experimental asthma. The present study addressed the hypothesis that ST2L impairs the therapeutic effects of CpG in a fungal model of asthma. C57BL/6 mice were sensitized to Aspergillus fumigatus and challenged via i.t. instillation with live A. fumigatus conidia. Mice were treated with IgG alone, anti-ST2L monoclonal antibody (mAb) alone, CpG alone, IgG plus CpG, or anti-ST2L mAb plus CpG every other day from day 14 to day 28 and investigated on day 28 after conidia. Lung ST2L and toll-like receptor 9 protein expression levels concomitantly increased in a time-dependent manner during fungal asthma. Therapeutic blockade of ST2L with an mAb attenuated key pathological features of this model. At subtherapeutic doses, neither anti-ST2L mAb nor CpG alone affected fungal asthma severity. However, airway hyperresponsiveness, mucus cell metaplasia, peribronchial fibrosis, and fungus retention were markedly reduced in asthmatic mice treated with the combination of both. Whole lung CXCL9 levels were significantly elevated in the combination group but not in the controls. Furthermore, in asthmatic mice treated with the combination therapy, dendritic cells generated significantly greater IL-12p70 with CpG in vitro compared with control dendritic cells. The combination of anti-ST2L mAb with CpG significantly attenuated experimental asthma, suggesting that targeting ST2L might enhance the therapeutic efficacy of CpG during allergic inflammation.
    American Journal Of Pathology 07/2011; 179(1):104-15. DOI:10.1016/j.ajpath.2011.03.032
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    ABSTRACT: The exaggerated expression of chitinase-like protein YKL-40, the human homologue of breast regression protein-39 (BRP-39), was reported in a number of diseases, including chronic obstructive pulmonary disease (COPD). However, the in vivo roles of YKL-40 in normal physiology or in the pathogenesis of specific diseases such as COPD remain poorly understood. We hypothesized that BRP-39/YKL-40 plays an important role in the pathogenesis of cigarette smoke (CS)-induced emphysema. To test this hypothesis, 10-week-old wild-type and BRP-39 null mutant mice (BRP-39(-/-)) were exposed to room air (RA) and CS for up to 10 months. The expression of BRP-39 was significantly induced in macrophages, airway epithelial cells, and alveolar Type II cells in the lungs of CS-exposed mice compared with RA-exposed mice, at least in part via an IL-18 signaling-dependent pathway. The null mutation of BRP-39 significantly reduced CS-induced bronchoalveolar lavage and tissue inflammation. However, CS-induced epithelial cell apoptosis and alveolar destruction were further enhanced in the absence of BRP-39. Consistent with these findings in mice, the tissue expression of YKL-40 was significantly increased in the lungs of current smokers compared with the lungs of ex-smokers or nonsmokers. In addition, serum concentrations of YKL-40 were significantly higher in smokers with COPD than in nonsmokers or smokers without COPD. These studies demonstrate a novel regulatory role of BRP-39/YKL-40 in CS-induced inflammation and emphysematous destruction. These studies also underscore that maintaining physiologic concentrations of YKL-40 in the lung is therapeutically important in preventing excessive inflammatory responses or emphysematous alveolar destruction.
    American Journal of Respiratory Cell and Molecular Biology 06/2011; 44(6):777-86. DOI:10.1165/rcmb.2010-0081OC
  • American Thoracic Society 2011 International Conference, May 13-18, 2011 • Denver Colorado; 05/2011
  • American Thoracic Society 2011 International Conference, May 13-18, 2011 • Denver Colorado; 05/2011
  • American Thoracic Society 2011 International Conference, May 13-18, 2011 • Denver Colorado; 05/2011
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    ABSTRACT: Asthma exacerbations remain a major unmet clinical need. The difficulty in obtaining airway tissue and bronchoalveolar lavage samples during exacerbations has greatly hampered study of naturally occurring exacerbations. This study was conducted to determine if mRNA profiling of peripheral blood mononuclear cells (PBMCs) could provide information on the systemic molecular pathways involved during asthma exacerbations. Over the course of one year, gene expression levels during stable asthma, exacerbation, and two weeks after an exacerbation were compared using oligonucleotide arrays. For each of 118 subjects who experienced at least one asthma exacerbation, the gene expression patterns in a sample of peripheral blood mononuclear cells collected during an exacerbation episode were compared to patterns observed in multiple samples from the same subject collected during quiescent asthma. Analysis of covariance identified genes whose levels of expression changed during exacerbations and returned to quiescent levels by two weeks. Heterogeneity among visits in expression profiles was examined using K-means clustering. Three distinct exacerbation-associated gene expression signatures were identified. One signature indicated that, even among patients without symptoms of respiratory infection, genes of innate immunity were activated. Antigen-independent T cell activation mediated by IL15 was also indicated by this signature. A second signature revealed strong evidence of lymphocyte activation through antigen receptors and subsequent downstream events of adaptive immunity. The number of genes identified in the third signature was too few to draw conclusions on the mechanisms driving those exacerbations. This study has shown that analysis of PBMCs reveals systemic changes accompanying asthma exacerbation and has laid the foundation for future comparative studies using PBMCs.
    PLoS ONE 01/2011; 6(7):e21902. DOI:10.1371/journal.pone.0021902
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    ABSTRACT: Nogo-B is a member of the reticulon family of proteins (RTN-4B) that is highly expressed in lung tissue; however, its function remains unknown. We show that mice with Th2-driven lung inflammation results in a loss of Nogo expression in airway epithelium and smooth muscle compared with nonallergic mice, a finding which is replicated in severe human asthma. Mice lacking Nogo-A/B (Nogo-KO) display an exaggerated asthma-like phenotype, and epithelial reconstitution of Nogo-B in transgenic mice blunts Th2-mediated lung inflammation. Microarray analysis of lungs from Nogo-KO mice reveals a marked reduction in palate lung and nasal clone (PLUNC) gene expression, and the levels of PLUNC are enhanced in epithelial Nogo-B transgenic mice. Finally, transgenic expression of PLUNC into Nogo-KO mice rescues the enhanced asthmatic-like responsiveness in these KO mice. These data identify Nogo-B as a novel protective gene expressed in lung epithelia, and its expression regulates the levels of the antibacterial antiinflammatory protein PLUNC.
    Journal of Experimental Medicine 10/2010; 207(12):2595-607. DOI:10.1084/jem.20100786
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    ABSTRACT: Fungi can exacerbate symptoms in patients with asthma. To our knowledge, genetic risk factors for fungal-associated asthma have not been described. We present here the cases of 6 children who carried the diagnosis of severe asthma with fungal sensitization, 3 of whom were treated with and responded clinically to itraconazole therapy. All 6 patients were heterozygous for a 24-base pair duplication in the CHIT1 gene, which has been associated with decreased levels of circulating chitotriosidase and susceptibility to fungal infection.
    PEDIATRICS 10/2010; 126(4):e982-5. DOI:10.1542/peds.2010-0321
  • American Thoracic Society 2010 International Conference, May 14-19, 2010 • New Orleans; 05/2010

Publication Stats

2k Citations
370.64 Total Impact Points

Institutions

  • 2004–2014
    • Yale-New Haven Hospital
      • Department of Pathology
      New Haven, Connecticut, United States
  • 2006–2013
    • Yale University
      • • Department of Internal Medicine
      • • Section of Pulmonary and Critical Care Medicine
      New Haven, Connecticut, United States
    • University of California, San Francisco
      San Francisco, California, United States