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  1. Article: CFTR heterozygosity in severe asthma with recurrent airway infections: a retrospective review.

    Priel, Eldar / Adatia, Adil / Kjarsgaard, Melanie / Nair, Parameswaran

    Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology

    2022  Volume 18, Issue 1, Page(s) 46

    Abstract: Rationale: Patients with asthma who have neutrophilic bronchitis may have an underlying cause leading to increased susceptibility to airway infections.: Methods: Retrospective review of patients with asthma who had a previous history of recurrent ... ...

    Abstract Rationale: Patients with asthma who have neutrophilic bronchitis may have an underlying cause leading to increased susceptibility to airway infections.
    Methods: Retrospective review of patients with asthma who had a previous history of recurrent exacerbations that had been associated with airway or sinus infections referred to a tertiary asthma center between 2005 and 2020. Demographics, clinical features, and airway inflammation type determined by sputum cytometry were compared between CFTR carriers and non-carriers. Multiple linear regression was used to identify clinical predictors of CFTR carrier status. Response to nebulized hypertonic saline was assessed by comparing the number of infective exacerbations before and after its initiation.
    Results: 75 patients underwent CFTR mutation testing. Of these, 13 (17%) were CFTR carriers. The most common mutation was [Formula: see text]F508. CFTR carriers were older (adjusted odds ratio 1.06 (CI 95% 1.01, 1.13)) and had more frequent flares requiring hospitalization (4.19 (1.34, 24.74)). Neutrophilic airway inflammation was the most common inflammatory subtype in CFTR carriers, though 8/13 also had eosinophilic bronchitis. Nebulized hypertonic saline was well tolerated by most and reduced the frequency of infective exacerbations.
    Conclusions: The prevalence of CFTR heterozygosity in this cohort with recurrent neutrophilic bronchitis is higher than in the general population. Respiratory disease in CFTR carriers is associated with older age and may cause significant morbidity. Airway neutrophilia is the most common inflammatory subtype, but > 50% had eosinophilic bronchitis requiring treatment. Hypertonic saline appears to be well tolerated and effective in reducing the number of infective exacerbations.
    Language English
    Publishing date 2022-06-06
    Publishing country England
    Document type Journal Article
    ZDB-ID 2434973-2
    ISSN 1710-1492 ; 1710-1484
    ISSN (online) 1710-1492
    ISSN 1710-1484
    DOI 10.1186/s13223-022-00684-0
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  2. Article ; Online: Specific Ventilation in Severe Asthma Evaluated with Noncontrast Tidal Breathing

    Capaldi, Dante P I / Konyer, Norman B / Kjarsgaard, Melanie / Dvorkin-Gheva, Anna / Dandurand, Ronald J / Nair, Parameswaran / Svenningsen, Sarah

    Radiology. Cardiothoracic imaging

    2024  Volume 5, Issue 6, Page(s) e230054

    Abstract: Purpose To determine if proton ( ...

    Abstract Purpose To determine if proton (
    MeSH term(s) Male ; Humans ; Female ; Middle Aged ; Protons ; Prospective Studies ; Asthma/diagnostic imaging ; Inflammation ; Biomarkers ; Magnetic Resonance Imaging/methods
    Chemical Substances Protons ; Biomarkers
    Language English
    Publishing date 2024-01-02
    Publishing country United States
    Document type Journal Article
    ISSN 2638-6135
    ISSN (online) 2638-6135
    DOI 10.1148/ryct.230054
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  3. Article ; Online: Sputum cytokines associated with raised FeNO after anti-IL5 biologic therapy in severe asthma.

    Hekking, Pieter-Paul / Zhang, Kayla / Garrido, Carmen Paz Venegas / Lopez-Rodriguez, Raquel / Kjarsgaard, Melanie / Mukherjee, Manali / Nair, Parameswaran

    Allergy

    2024  

    Language English
    Publishing date 2024-01-10
    Publishing country Denmark
    Document type Journal Article
    ZDB-ID 391933-x
    ISSN 1398-9995 ; 0105-4538
    ISSN (online) 1398-9995
    ISSN 0105-4538
    DOI 10.1111/all.16011
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  4. Article ; Online: Effects of Dupilumab on Mucus Plugging and Ventilation Defects in Patients with Moderate-to-Severe Asthma: A Randomized, Double-Blind, Placebo-Controlled Trial.

    Svenningsen, Sarah / Kjarsgaard, Melanie / Haider, Ehsan / Venegas, Carmen / Konyer, Norman / Friedlander, Yonni / Nasir, Neha / Boylan, Colm / Kirby, Miranda / Nair, Parameswaran

    American journal of respiratory and critical care medicine

    2023  Volume 208, Issue 9, Page(s) 995–997

    MeSH term(s) Humans ; Antibodies, Monoclonal, Humanized/therapeutic use ; Asthma/drug therapy ; Double-Blind Method ; Injections, Subcutaneous ; Mucus ; Severity of Illness Index ; Treatment Outcome
    Chemical Substances Antibodies, Monoclonal, Humanized ; dupilumab (420K487FSG)
    Language English
    Publishing date 2023-08-21
    Publishing country United States
    Document type Randomized Controlled Trial ; Letter ; Research Support, Non-U.S. Gov't
    ZDB-ID 1180953-x
    ISSN 1535-4970 ; 0003-0805 ; 1073-449X
    ISSN (online) 1535-4970
    ISSN 0003-0805 ; 1073-449X
    DOI 10.1164/rccm.202306-1102LE
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  5. Article ; Online: Phase-Resolved Functional Lung (PREFUL) MRI to Quantify Ventilation: Feasibility and Physiological Relevance in Severe Asthma.

    Friedlander, Yonni / Munidasa, Samal / Thakar, Ashutosh / Ragunayakam, Nandhitha / Venegas, Carmen / Kjarsgaard, Melanie / Zanette, Brandon / Capaldi, Dante P I / Santyr, Giles / Nair, Parameswaran / Svenningsen, Sarah

    Academic radiology

    2024  

    Abstract: Rationale and objectives: Emergent evidence in several respiratory diseases supports translational potential for Phase-Resolved Functional Lung (PREFUL) MRI to spatially quantify ventilation but its feasibility and physiological relevance have not been ... ...

    Abstract Rationale and objectives: Emergent evidence in several respiratory diseases supports translational potential for Phase-Resolved Functional Lung (PREFUL) MRI to spatially quantify ventilation but its feasibility and physiological relevance have not been demonstrated in patients with asthma. This study compares PREFUL-derived ventilation defect percent (VDP) in severe asthma patients to healthy controls and measures its responsiveness to bronchodilator therapy and relation to established measures of airways disease.
    Materials and methods: Forty-one adults with severe asthma and seven healthy controls performed same-day free-breathing
    Results: PREFUL VDP measured pre-bronchodilator (19.1% [7.4-43.3], p = 0.0002) and post-bronchodilator (16.9% [6.1-38.4], p = 0.0007) were significantly greater than that of healthy controls (7.5% [3.7-15.5]) and was significantly decreased post-bronchodilator (from 21.9% [10.1-36.9] to 16.9% [6.1-38.4], p = 0.0053). PREFUL VDP was correlated with spirometry (FEV
    Conclusion: PREFUL-derived VDP is responsive to bronchodilator therapy in asthma and is associated with measures of airflow obstruction and small airway dysfunction. These findings validate PREFUL VDP as a physiologically relevant and accessible ventilation imaging outcome measure in asthma.
    Language English
    Publishing date 2024-02-19
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1355509-1
    ISSN 1878-4046 ; 1076-6332
    ISSN (online) 1878-4046
    ISSN 1076-6332
    DOI 10.1016/j.acra.2024.01.039
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  6. Article ; Online: Phosphoinositide-3 kinase activity in severe eosinophilic asthma with recurrent airway infections and neutrophilic exacerbations.

    Bhalla, Anurag / Radford, Katherine / Son, Kiho / Zhang, Kayla / Huang, Chynna / Kjarsgaard, Melanie / LaVigne, Nicola / Brautigam, Zachary / Svenningsen, Sarah / Paré, Guillaume / Mukherjee, Manali / Nair, Parameswaran

    Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology

    2024  

    Language English
    Publishing date 2024-03-11
    Publishing country England
    Document type Journal Article
    ZDB-ID 645204-8
    ISSN 1365-2222 ; 0954-7894 ; 0960-2178
    ISSN (online) 1365-2222
    ISSN 0954-7894 ; 0960-2178
    DOI 10.1111/cea.14471
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  7. Article ; Online: Effects of Anti-T2 Biologic Treatment on Lung Ventilation Evaluated by MRI in Adults With Prednisone-Dependent Asthma.

    Svenningsen, Sarah / Eddy, Rachel L / Kjarsgaard, Melanie / Parraga, Grace / Nair, Parameswaran

    Chest

    2020  Volume 158, Issue 4, Page(s) 1350–1360

    Abstract: Background: The functional consequence of airway obstruction in asthma can be regionally measured using inhaled gas MRI. Ventilation defects visualized by MRI persist post-bronchodilator in patients with severe asthma with uncontrolled sputum ... ...

    Abstract Background: The functional consequence of airway obstruction in asthma can be regionally measured using inhaled gas MRI. Ventilation defects visualized by MRI persist post-bronchodilator in patients with severe asthma with uncontrolled sputum eosinophilia and may be due to eosinophil-driven airway pathology that is responsive to "anti-T2" therapy.
    Research question: Do anti-T2 therapies that clear eosinophils from the airway lumen decrease ventilation defects, measured by inhaled gas MRI, in adults with prednisone-dependent asthma?
    Study design and methods: Inhaled hyperpolarized gas MRI was performed before and after bronchodilation in 10 prednisone-dependent patients with asthma with uncontrolled eosinophilic bronchitis (sputum eosinophils ≥3%) at baseline and 558 (100-995) days later when their eosinophilic bronchitis had been controlled (sputum eosinophils <3%) by additional anti-T2 therapy. The effect of anti-T2 therapy on ventilation defects, quantified as the MRI ventilation-defect-percent (VDP), was evaluated before and after bronchodilation for all patients and compared between patients dichotomized based on the median percentage of sputum eosinophils at baseline (15.8%).
    Results: MRI VDP was improved pre- (ΔVDP
    Interpretation: Controlling sputum eosinophilia with anti-T2 therapies improves ventilation defects, measured by inhaled gas MRI, in adults with prednisone-dependent asthma.
    MeSH term(s) Adult ; Asthma/classification ; Asthma/complications ; Asthma/drug therapy ; Asthma/physiopathology ; Biological Therapy ; Bronchitis/complications ; Bronchodilator Agents/therapeutic use ; Eosinophilia/complications ; Eosinophils ; Female ; Glucocorticoids/therapeutic use ; Humans ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Prednisone/therapeutic use ; Prospective Studies ; Pulmonary Ventilation ; Severity of Illness Index ; Sputum/cytology
    Chemical Substances Bronchodilator Agents ; Glucocorticoids ; Prednisone (VB0R961HZT)
    Language English
    Publishing date 2020-05-16
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1032552-9
    ISSN 1931-3543 ; 0012-3692
    ISSN (online) 1931-3543
    ISSN 0012-3692
    DOI 10.1016/j.chest.2020.04.056
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  8. Article ; Online: Effect of dupilumab on sputum eosinophils in patients with moderate-to-severe asthma.

    Svenningsen, Sarah / Kjarsgaard, Melanie / Zhang, Kayla / Serajeddini, Hana / Garrido, Carmen Venegas / Bhalla, Anurag / Radford, Katherine / Huang, Chynna / Ho, Terence / Ragunayakam, Nandhitha / Thakar, Ashutosh / Radadia, Nisarg / Mukherjee, Manali / Nair, Parameswaran

    Allergy

    2023  Volume 79, Issue 2, Page(s) 509–513

    MeSH term(s) Humans ; Eosinophils ; Sputum ; Asthma/diagnosis ; Asthma/drug therapy ; Antibodies, Monoclonal, Humanized/pharmacology ; Antibodies, Monoclonal, Humanized/therapeutic use
    Chemical Substances dupilumab (420K487FSG) ; Antibodies, Monoclonal, Humanized
    Language English
    Publishing date 2023-09-26
    Publishing country Denmark
    Document type Letter
    ZDB-ID 391933-x
    ISSN 1398-9995 ; 0105-4538
    ISSN (online) 1398-9995
    ISSN 0105-4538
    DOI 10.1111/all.15901
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  9. Article: Underestimation of airway luminal eosinophilia by quantitative sputum cytometry.

    Kjarsgaard, Melanie / Adatia, Adil / Bhalla, Anurag / LaVigne, Nicola / Radford, Katherine / Huang, Chynna / Mukherjee, Manali / Nair, Parameswaran

    Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology

    2021  Volume 17, Issue 1, Page(s) 63

    Abstract: Rationale: On Wright-stained sputum cytospins, eosinophil differential of ≥ 1.2% is considered abnormal, and ≥ 2.3% identifies an eosinophilic endotype. We hypothesized that failure to consider free eosinophil granules (FEG), and the re-emergence ( ... ...

    Abstract Rationale: On Wright-stained sputum cytospins, eosinophil differential of ≥ 1.2% is considered abnormal, and ≥ 2.3% identifies an eosinophilic endotype. We hypothesized that failure to consider free eosinophil granules (FEG), and the re-emergence (unmasking) of eosinophilia due to various reasons underestimate the prevalence of the eosinophilic endotype.
    Methods: This is a retrospective analysis of our Institutional Review Board-approved clinical sputum database. Of the 24,176 examinations of sputa from patients with various airway diseases, 17,693 were viable cell counts from 9570 patients (6604 on a single occasion, 2967 from multiple occasions). The prevalence of intact eosinophil % at 1.2 and 2.3% thresholds was first examined. Then, additional evidence of eosinophilia was assessed by semi-quantitative enumeration of FEGs. In those patients whose sputa were examined on multiple occasions (at the time of an exacerbation or after corticosteroid dose was reduced), re-emergence (unmasking) of eosinophilia was assessed .
    Results: Using the threshold of eosinophilia ≥ 1.2%, 6289/17693 (35.6%) of sputa were classified as eosinophilic. This increased to 7850/17693 (44.4%) when the presence of FEGs was considered. Using the threshold of eosinophilia ≥ 2.3%, 4647/17693 (26.3%) of sputa were classified as eosinophilic. This increased to 5435/17693 (30.7%) when the presence of FEG were considered. Extrapolating from the prevalence of re-emergence observed in the 2967 patients who had sputa examined on multiple occasions to the whole sample, we estimated that eosinophilia at 1.2% threshold would be observed in at least 60% of the samples, and a clinically relevant eosinophilia at 2.3% threshold would be observed in at least 48.5% of the samples.
    Conclusions: Using a large sputum cytometry clinical database (17,693 viable cell counts), we demonstrate that a single time point intact cell count underestimates the prevalence of eosinophilia in a variety of airway diseases. The prevalence of eosinophilia increases from 35.6 to 60% (40% underestimation) at the 1.2% threshold, and from 26.3 to 48.5% (45% underestimation) at the 2.3% clinically relevant threshold, when free granules and a second examination are considered. This has important implications to identify the eosinophilic and Th2 high endotype both for clinical trials of anti-eosinophil therapies, and to select patients who may respond well to glucocorticosteroids and anti-IL5 therapies.
    Language English
    Publishing date 2021-07-05
    Publishing country England
    Document type Journal Article
    ZDB-ID 2434973-2
    ISSN 1710-1492 ; 1710-1484
    ISSN (online) 1710-1492
    ISSN 1710-1484
    DOI 10.1186/s13223-021-00567-w
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  10. Article ; Online: Iron in airway macrophages and infective exacerbations of chronic obstructive pulmonary disease.

    Ho, Terence / Nichols, Matthew / Nair, Gayatri / Radford, Katherine / Kjarsgaard, Melanie / Huang, Chynna / Bhalla, Anurag / Lavigne, Nicola / Mukherjee, Manali / Surette, Michael / Macri, Joseph / Nair, Parameswaran

    Respiratory research

    2022  Volume 23, Issue 1, Page(s) 8

    Abstract: Background: Excess pulmonary iron has been implicated in the pathogenesis of lung disease, including asthma and COPD. An association between higher iron content in sputum macrophages and infective exacerbations of COPD has previously been demonstrated.!# ...

    Abstract Background: Excess pulmonary iron has been implicated in the pathogenesis of lung disease, including asthma and COPD. An association between higher iron content in sputum macrophages and infective exacerbations of COPD has previously been demonstrated.
    Objectives: To assess the mechanisms of pulmonary macrophage iron sequestration, test the effect of macrophage iron-loading on cellular immune function, and prospectively determine if sputum hemosiderin index can predict infectious exacerbations of COPD.
    Methods: Intra- and extracellular iron was measured in cell-line-derived and in freshly isolated sputum macrophages under various experimental conditions including treatment with exogenous IL-6 and hepcidin. Bacterial uptake and killing were compared in the presence or absence of iron-loading. A prospective cohort of COPD patients with defined sputum hemosiderin indices were monitored to determine the annual rate of severe infectious exacerbations.
    Results: Gene expression studies suggest that airway macrophages have the requisite apparatus of the hepcidin-ferroportin axis. IL-6 and hepcidin play roles in pulmonary iron sequestration, though IL-6 appears to exert its effect via a hepcidin-independent mechanism. Iron-loaded macrophages had reduced uptake of COPD-relevant organisms and were associated with higher growth rates. Infectious exacerbations were predicted by sputum hemosiderin index (β = 0.035, p = 0.035).
    Conclusions: We demonstrate in-vitro and population-level evidence that excess iron in pulmonary macrophages may contribute to recurrent airway infection in COPD. Specifically, IL-6-dependent iron sequestration by sputum macrophages may result in immune cell dysfunction and ultimately lead to increased frequency of infective exacerbation.
    MeSH term(s) Aged ; Female ; Follow-Up Studies ; Humans ; Iron/metabolism ; Leukocyte Count ; Macrophages, Alveolar/metabolism ; Macrophages, Alveolar/pathology ; Male ; Prospective Studies ; Pulmonary Disease, Chronic Obstructive/metabolism ; Pulmonary Disease, Chronic Obstructive/pathology ; Recurrence ; Sputum/metabolism
    Chemical Substances Iron (E1UOL152H7)
    Language English
    Publishing date 2022-01-12
    Publishing country England
    Document type Journal Article
    ZDB-ID 2041675-1
    ISSN 1465-993X ; 1465-993X
    ISSN (online) 1465-993X
    ISSN 1465-993X
    DOI 10.1186/s12931-022-01929-7
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