Keith C Meyer

University of Wisconsin–Madison, Madison, Wisconsin, United States

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Publications (90)416.32 Total impact

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    ABSTRACT: BACKGROUND: Nintedanib (formerly known as BIBF 1120) is an intracellular inhibitor that targets multiple tyrosine kinases. A phase 2 trial suggested that treatment with 150 mg of nintedanib twice daily reduced lung-function decline and acute exacerbations in patients with idiopathic pulmonary fibrosis. METHODS: We conducted two replicate 52-week, randomized, double-blind, phase 3 trials (INPULSIS-1 and INPULSIS-2) to evaluate the efficacy and safety of 150 mg of nintedanib twice daily as compared with placebo in patients with idiopathic pulmonary fibrosis. The primary end point was the annual rate of decline in forced vital capacity (FVC). Key secondary end points were the time to the first acute exacerbation and the change from baseline in the total score on the St. George's Respiratory Questionnaire, both assessed over a 52-week period. RESULTS: A total of 1066 patients were randomly assigned in a 3:2 ratio to receive nintedanib or placebo. The adjusted annual rate of change in FVC was -114.7 ml with nintedanib versus -239.9 ml with placebo (difference, 125.3 ml; 95% confidence interval [CI], 77.7 to 172.8; P<0.001) in INPULSIS-1 and -113.6 ml with nintedanib versus -207.3 ml with placebo (difference, 93.7 ml; 95% CI, 44.8 to 142.7; P<0.001) in INPULSIS-2. In INPULSIS-1, there was no significant difference between the nintedanib and placebo groups in the time to the first acute exacerbation (hazard ratio with nintedanib, 1.15; 95% CI, 0.54 to 2.42; P=0.67); in INPULSIS-2, there was a significant benefit with nintedanib versus placebo (hazard ratio, 0.38; 95% CI, 0.19 to 0.77; P=0.005). The most frequent adverse event in the nintedanib groups was diarrhea, with rates of 61.5% and 18.6% in the nintedanib and placebo groups, respectively, in INPULSIS-1 and 63.2% and 18.3% in the two groups, respectively, in INPULSIS-2. CONCLUSIONS: In patients with idiopathic pulmonary fibrosis, nintedanib reduced the decline in FVC, which is consistent with a slowing of disease progression; nintedanib was frequently associated with diarrhea, which led to discontinuation of the study medication in less than 5% of patients.
    New England Journal of Medicine 05/2014; 370(22):2071-82. · 51.66 Impact Factor
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    ABSTRACT: How elevated temperature is generated during airway infections represents a hitherto unresolved physiological question. We hypothesized that innate immune defence mechanisms would increase luminal airway temperature during pulmonary infection. We determined the temperature in the exhaled air of cystic fibrosis (CF) patients. To further test our hypothesis, a pouch inflammatory model using neutrophil elastase-deficient mice was employed. Next, the impact of temperature changes on the dominant CF pathogen Pseudomonas aeruginosa growth was tested by plating method and RNAseq. Here we show a temperature of ~38°C in neutrophil-dominated mucus plugs of chronically infected CF patients and implicate neutrophil elastase:α1-proteinase inhibitor complex formation as a relevant mechanism for the local temperature rise. Gene expression of the main pathogen in CF, P. aeruginosa, under anaerobic conditions at 38°C vs 30°C revealed increased virulence traits and characteristic cell wall changes. Neutrophil elastase mediates increase in airway temperature, which may contribute to P. aeruginosa selection during the course of chronic infection in CF.
    Journal of cystic fibrosis: official journal of the European Cystic Fibrosis Society 04/2014; · 3.19 Impact Factor
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    ABSTRACT: Background How elevated temperature is generated during airway infections represents a hitherto unresolved physiological question. We hypothesized that innate immune defence mechanisms would increase luminal airway temperature during pulmonary infection. Methods We determined the temperature in the exhaled air of cystic fibrosis (CF) patients. To further test our hypothesis, a pouch inflammatory model using neutrophil elastase-deficient mice was employed. Next, the impact of temperature changes on the dominant CF pathogen Pseudomonas aeruginosa growth was tested by plating method and RNAseq. Results Here we show a temperature of ~ 38 °C in neutrophil-dominated mucus plugs of chronically infected CF patients and implicate neutrophil elastase:α1-proteinase inhibitor complex formation as a relevant mechanism for the local temperature rise. Gene expression of the main pathogen in CF, P. aeruginosa, under anaerobic conditions at 38 °C vs 30 °C revealed increased virulence traits and characteristic cell wall changes. Conclusion Neutrophil elastase mediates increase in airway temperature, which may contribute to P. aeruginosa selection during the course of chronic infection in CF.
    Journal of Cystic Fibrosis. 01/2014;
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    ABSTRACT: Many risk factors and post-transplant events have been linked to the development of bronchiolitis obliterans syndrome. Evolving research suggests that the development of cell-mediated and humoral reactivity to self-antigens (collagen V, K-α1 tubulin) in the lung allograft may play a very significant role in the bron-chiolar inflammation and fibrosis that lead to obliterative bronchiolitis and progres-sive graft dysfunction and loss. Alloimmune and autoimmune mechanisms likely work together to mediate chronic lung allograft rejection. This chapter examines the role of autoimmunity in bronchiolitis obliterans syndrome with a focus on the role of Th17 lymphocytes, IL-17, and immune regulatory mechanisms in the develop-ment and progression of obliterative bronchiolitis.
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    ABSTRACT: Although survival after lung transplantation has improved significantly during the last decade, chronic rejection is thought to be the major cause of late mortality. The physiologic hallmark of chronic rejection has been a persistent fall in forced expiratory volume in 1 second associated with an obstructive ventilatory defect, for which the term bronchiolitis obliterans syndrome (BOS) was defined to allow a uniformity of description and grading of severity throughout the world. Although BOS was generally thought to be irreversible, recent evidence suggests that some patients with BOS may respond to azithromycin with > 10% improvement in their forced expiratory volume in 1 second. In addition, a restrictive form of chronic rejection has recently been described that does not fit the strict definition of BOS as an obstructive defect. Hence, the term chronic lung allograft dysfunction (CLAD) has been introduced to cover all forms of graft dysfunction, but CLAD has yet to be defined. We propose a definition of CLAD and a flow chart that may facilitate recognition of the different phenotypes of CLAD that can complicate the clinical course of lung transplant recipients.
    The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 10/2013; · 3.54 Impact Factor
  • Keith C Meyer, Ganesh Raghu
    American Journal of Respiratory and Critical Care Medicine 07/2013; 188(1):113-4. · 11.04 Impact Factor
  • American Journal of Respiratory and Critical Care Medicine 07/2013; 188(1):111. · 11.04 Impact Factor
  • Keith C Meyer, Ganesh Raghu
    American Journal of Respiratory and Critical Care Medicine 04/2013; 187(7):777-8. · 11.04 Impact Factor
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    Keith C Meyer
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    ABSTRACT: Lung transplantation may be the only intervention that can prolong survival and improve quality of life for those individuals with advanced lung disease who are acceptable candidates for the procedure. However, these candidates may be extremely ill and require ventilator and/or circulatory support as a bridge to transplantation, and lung transplantation recipients are at risk of numerous post-transplant complications that include surgical complications, primary graft dysfunction, acute rejection, opportunistic infection, and chronic lung allograft dysfunction (CLAD), which may be caused by chronic rejection. Many advances in pre- and post-transplant management have led to improved outcomes over the past decade. These include the creation of sound guidelines for candidate selection, improved surgical techniques, advances in donor lung preservation, an improving ability to suppress and treat allograft rejection, the development of prophylaxis protocols to decrease the incidence of opportunistic infection, more effective therapies for treating infectious complications, and the development of novel therapies to treat and manage CLAD. A major obstacle to prolonged survival beyond the early post-operative time period is the development of bronchiolitis obliterans syndrome (BOS), which is the most common form of CLAD. This manuscript discusses recent and evolving advances in the field of lung transplantation.
    F1000prime reports. 01/2013; 5:16.
  • 01/2013: pages 183-198; , ISBN: 978-1-4614-7635-1
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    ABSTRACT: Despite its incorporation into research studies, the safety aspects of segmental allergen bronchoprovocation and differences in cellular response among different allergens have received limited consideration. We performed 87 segmental challenges in 77 allergic asthma subjects. Allergen dose was based on each subject's response to whole lung allergen challenge. Bronchoalveolar lavage was performed at 0 and 48 hours. Safety indicators included spirometry, oxygen saturation, heart rate, and symptoms. Among subjects challenged with ragweed, cat dander, or house dust mite, there were no differences in safety indicators. Subjects demonstrated a modest oxygen desaturation and tachycardia during the procedure that returned to normal prior to discharge. We observed a modest reduction in forced vital capacity and forced expiratory volume in one second following bronchoscopy. The most common symptoms following the procedure were cough, sore throat and fatigue. Total bronchoalveolar lavage fluid cell numbers increased from 13±4 to 106±108×10(4) per milliliter and eosinophils increased from 1±2 to 44±20 percent, with no significant differences among the three allergens. In mild allergic asthma, segmental allergen bronchoprovocation, using individualized doses of aeroallergens, was safe and yielded similar cellular responses.
    PLoS ONE 01/2013; 8(1):e51963. · 3.73 Impact Factor
  • Chest 11/2012; 142(5):1284-8. · 5.85 Impact Factor
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    ABSTRACT: Immunosuppressive pharmacologic agents prescribed to patients with diffuse interstitial and inflammatory lung disease and lung transplant recipients are associated with potential risks for adverse reactions. Strategies for minimizing such risks include administering these drugs according to established, safe protocols; monitoring to detect manifestations of toxicity; and patient education. Hence, an evidence-based guideline for physicians can improve safety and optimize the likelihood of a successful outcome. To maximize the likelihood that these agents will be used safely, the American College of Chest Physicians established a committee to examine the clinical evidence for the administration and monitoring of immunosuppressive drugs (with the exception of corticosteroids) to identify associated toxicities associated with each drug and appropriate protocols for monitoring these agents. Committee members developed and refined a series of questions about toxicities of immunosuppressives and current approaches to administration and monitoring. A systematic review was carried out by the American College of Chest Physicians. Committee members were supplied with this information and created this evidence-based guideline. It is hoped that these guidelines will improve patient safety when immunosuppressive drugs are given to lung transplant recipients and to patients with diffuse interstitial lung disease.
    Chest 11/2012; 142(5):e1S-e111S. · 5.85 Impact Factor
  • Keith C Meyer, Jennifer Bierach
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    ABSTRACT: This article focuses on issues of safety and monitoring when immunosuppressive pharmacologic therapies are prescribed for the treatment of connective tissue disease (CTD)-associated interstitial pneumonias, vasculitides, and bronchiolitis. Prospective, randomized placebo-controlled clinical trials have yet to be performed to evaluate the efficacy and safety of various immunosuppressive agents used to treat patients with CTD-interstitial lung disease or idiopathic interstitial pneumonias other than idiopathic pulmonary fibrosis (idiopathic usual interstitial pneumonia) that are not associated with the presence of CTD. Knowledge of their potential toxicities and interactions with other drugs combined with the adoption of a systematic approach to monitoring therapy can minimize life-threatening reactions.
    Immunology and allergy clinics of North America 11/2012; 32(4):633-669. · 3.18 Impact Factor
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    ABSTRACT: SESSION TYPE: COPD: Therapeutic OptionsPRESENTED ON: Sunday, October 21, 2012 at 10:30 AM - 11:45 AMPURPOSE: The NETT demonstrated improved pulmonary function, quality of life and survival advantage with LVRS. As the LAS shifted the diagnosis of lung transplant recipients, more consideration was given to LVRS. Since 2008, all patients with emphysema referred for lung transplantation were screened for LVRS. We describe our consecutive series of patients undergoing LVRS from January 2008 to December 2011.METHODS: Retrospective analysis of all patients who underwent LVRS during study time period. Patients were referred directly for LVRS or for transplantation and found to be candidates. Standard NETT criteria and workup were used for patient selection. LOS, ICU stay morbidity and mortality were determined. Quantitative improvement in pulmonary function was assessed at 3 months post procedure with paired student's t-test. Change oxygen requirement was assessed with fissures exact test. Survival was assessed with Kaplan Meier survival curves.RESULTS: LVRS was performed on 30 patients during study period.Mean age was 61. Mean pre-operative FEV1and FEV1% were 790ml and 26% predicted, respectively.The median ICU stay was 0 days (mean of 1.7), median LOS was 8 days. Two patients were discharged to skilled nursing facilities. Readmission rate was 7%. 30 and 90-day, 1 and three year mortality were zero. No patients have undergone transplantation. Mean improvement in FEV1 was 512 ml. (p<0.005), a mean increase of 61.4%. 92.6% had decreased oxygen needs and 17/27 (63%) had no supplemental oxygen needs post procedure.CONCLUSIONS: LVRS results in significant improvement in FEV1 and decreased need for supplemental oxygen that has not been replicated with bronchoscopic techniques. This can be accomplished with acceptable morbidity and very low mortality. This study is unique as all procedures were performed after the adoption of the LAS.CLINICAL IMPLICATIONS: LVRS should be more broadly offered to appropriate patients with emphysema who may have previously been transplant candidates.DISCLOSURE: The following authors have nothing to disclose: James Maloney, Nicole Strieter, Keith Meyer, Tiffany Mack, Richard CornwellNo Product/Research Disclosure InformationUniversity of Wisconsin Department of Surgery, Madison, WI.
    Chest 10/2012; 142(4_MeetingAbstracts):741A. · 5.85 Impact Factor
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    ABSTRACT: BACKGROUND: Neutrophils sequestered in lower respiratory tract secretions in the inflamed lung may undergo apoptosis and/or necrosis and release toxic cellular contents that can injure airways or parenchyma. This study examined the viability of neutrophils retrieved from the proximal airways of lung transplant recipients with bacterial tracheobronchitis. METHODS: Integrity and stability of intracellular proteins in neutrophils from proximal airways and peripheral blood from lung transplant recipients with bacterial tracheobronchitis were analyzed via Western blot analysis and determination of neutrophil viability by morphologic appearance and flow cytometry. RESULTS: Neutrophils in tracheobronchial secretions from lung transplant recipients with cystic fibrosis who had normal chest radiographic imaging but bronchoscopic evidence of purulent tracheobronchitis post-transplant were necrotic and associated with degradation of intracellular protein annexin 1. The neutrophil influx was compartmentalized to large airways and not detected in peripheral bronchoalveolar airspaces sampled via bronchoalveolar lavage. Peripheral blood neutrophils from healthy subjects cultured in vitro demonstrated that annexin 1 degradation, particularly to a 33 kDa annexin 1 breakdown product (A1-BP), was associated with neutrophil necrosis, but not apoptosis. Although annexin 1 degradation was not specific to neutrophil necrosis, it was a sensitive marker of intracellular protein degradation associated with neutrophil necrosis. Annexin 1 degradation to 33 kDa A1-BP was not observed in peripheral blood neutrophils from healthy subjects, but annexin 1 appeared to be degraded in peripheral blood neutrophils of lung transplant recipients despite a normal morphologic appearance of these cells. CONCLUSIONS: Neutrophils were necrotic from the proximal airways of lung transplant recipients with bacterial tracheobronchitis, and this process may begin when neutrophils are still in the systemic circulation prior to sequestration in inflamed airways. Annexin 1 degradation to 33 kDa A1-BP may be useful as a sensitive marker to detect neutrophil necrosis.
    BMC Pulmonary Medicine 08/2012; 12(1):44. · 2.76 Impact Factor
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    ABSTRACT: OBJECTIVE: To examine the incidence of recurrent Clostridium difficile infection in patients with cystic fibrosis (CF), including patients who had undergone lung transplantation, and review clinical findings in hospitalized patients with C. difficile colitis. METHODS: A retrospective chart review was performed to examine the clinical presentation and management of patients with cystic fibrosis (CF) who received care at the University of Wisconsin Hospital and Clinics (UWHC) from 1994 to 2011 and were prospectively identified with C. difficile colitis. RESULTS: Ten cases of C. difficile associated disease (CDAD) occurred in patients with CF followed by our Adult CF Center over a period of 17years, and 4 patients were bilateral lung transplant recipients. Two of the lung transplant recipients had recurrent CDAD that lead to fulminant pancolitis, surgical intervention, and shock. Two patients in the non-transplant group experienced recurrent C. difficile infection that led to fulminant pancolitis with associated systemic inflammatory response syndrome and required colectomy. CONCLUSIONS: C. difficile colitis can cause life threatening illness in patients with CF, and symptoms may be subtle and/or atypical and lead to significant delay in diagnosis. Patients with recurrent C. difficile colitis are at high risk of fatal outcome, and empiric therapy should be considered for patients with previous C. difficile colitis even in the absence of disease when broad-spectrum antibiotics are given to treat bacterial infection.
    Journal of cystic fibrosis: official journal of the European Cystic Fibrosis Society 06/2012; · 3.19 Impact Factor
  • Keith C Meyer
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    ABSTRACT: This review seeks to inform readers of evolving concepts of ageing-associated risks for developing interstitial lung disease (ILD) and current approaches to the diagnosis and management of ILD in elderly patients. Various aspects of cellular and immune senescence have been identified that may explain the increased susceptibility of the elderly to developing fibrotic lung disease. New guidelines have been recently published concerning the diagnosis and management of idiopathic pulmonary fibrosis (IPF), which is highly prevalent in elderly patients. Nontransplant therapies that can have a significant impact on disease progression for patients with IPF have yet to be identified. Additionally, evidence is accumulating that abnormal gastroesophageal reflux and microaspiration may play a role in IPF pathogenesis. High-resolution computed tomographic scanning of the thorax can play a key role in making a specific ILD diagnosis and be used to make a confident diagnosis of various forms of ILD, especially IPF, when combined with a consistent clinical presentation. Management of ILD in the elderly should be not only disease specific but potentially therapeutic, and supportive interventions should be tailored to each individual patient and not entail significant risk of adverse complications, especially for the frail elderly patient.
    Current opinion in pulmonary medicine 05/2012; 18(5):483-92. · 3.12 Impact Factor
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    ABSTRACT: The clinical utility of bronchoalveolar lavage fluid (BAL) cell analysis for the diagnosis and management of patients with interstitial lung disease (ILD) has been a subject of debate and controversy. The American Thoracic Society (ATS) sponsored a committee of international experts to examine all relevant literature on BAL in ILD and provide recommendations concerning the use of BAL in the diagnosis and management of patients with suspected ILD. To provide recommendations for (1) the performance and processing of BAL and (2) the interpretation of BAL nucleated immune cell patterns and other BAL characteristics in patients with suspected ILD. A pragmatic systematic review was performed to identify unique citations related to BAL in patients with ILD that were published between 1970 and 2006. The search was updated during the guideline development process to include published literature through March 2011. This is the evidence upon which the committee's conclusions and recommendations are based. Recommendations for the performance and processing of BAL, as well as the interpretation of BAL findings, were formulated by the committee. When used in conjunction with comprehensive clinical information and adequate thoracic imaging such as high-resolution computed tomography of the thorax, BAL cell patterns and other characteristics frequently provide useful information for the diagnostic evaluation of patients with suspected ILD.
    American Journal of Respiratory and Critical Care Medicine 05/2012; 185(9):1004-14. · 11.04 Impact Factor
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    ABSTRACT: This study investigated whether dietary supplementation of polyphenolics-rich grape extract (GE) could attenuate endotoxin-induced serum secretory phospholipase A(2) (sPLA(2)) activity, a modulator of inflammation. Male Sprague-Dawley rats were fed a control diet or the diet supplemented with polyphenolic-rich GE (100 or 300 mg/kg daily) for 3 wk prior to intraperitoneal injection of 3 or 15 mg/kg LPS. A fluorometric assay was used to measure serum sPLA(2) activity during a 5-d period before and after LPS injection. Body weight, hematocrit, and serum C-reactive protein level were also measured. Administration of LPS induced a rapid increase in sPLA(2) activity, which peaked 1 to 2 d after LPS injection and resolved to near-baseline values on days 4 to 5. Marked declines in body weight and hematocrit, increases in C-reactive protein levels, and effects on health status also occurred. GE supplementation significantly attenuated the LPS-induced increase in sPLA(2) activity and decline in hematocrit, but its effects on the loss of body weight and C-reactive protein levels were not significant. Among the measurements, serum sPLA(2) was the only marker that showed a dose-dependent response to both LPS and GE supplementation. The current findings show that oral consumption of polyphenolic-rich GE suppresses endotoxin-induced sPLA(2) activity.
    Comparative medicine 01/2012; 62(4):271-8. · 1.12 Impact Factor

Publication Stats

2k Citations
416.32 Total Impact Points

Institutions

  • 1989–2014
    • University of Wisconsin–Madison
      • • Department of Medicine
      • • Division of Cardiothoracic Surgery
      • • Division of Pulmonary and Critical Care Medicine
      • • Department of Surgery
      • • Laboratory of Developmental Biology
      Madison, Wisconsin, United States
  • 2013
    • Martin Luther University of Halle-Wittenberg
      • Institute for Hygiene
      Halle-on-the-Saale, Saxony-Anhalt, Germany
  • 2002–2010
    • University of Tuebingen
      • Institute of Medical Microbiology and Hygiene
      Tübingen, Baden-Wuerttemberg, Germany
  • 2009
    • University of Cincinnati
      Cincinnati, Ohio, United States
  • 2008
    • UW Health
      Madison, Wisconsin, United States
  • 2007
    • St. Mary's Hospital (WI, USA)
      Madison, Wisconsin, United States