My primary research focuses on clinical and translational asthma research, with three main foci of investigation: (i) asthma genetics and personalized medicine; (ii) clinical trials in asthma; and (iii) Churg-Strauss Syndrome. Regarding the genetics of asthma, I have investigated the role of numerous candidate gene polymorphisms in the pathogenesis and management of asthma. I was the Principal Investigator of the Lancet-published, NHLBI-funded Asthma Clinical Research Network’s LARGE trial, which prospectively investigated the effect of beta-adrenergic receptor polymorphisms on the asthmatic response to salmeterol. I also led a recently completed Partners Genetics Enters Medicine Initiative funded trial examining genotype-stratified treatment with anticholinergics vs. beta-agonists (long acting) and exacerbations (GABLE) in asthma (currently undergoing analysis).
I was a site Principal Investigator examining the effects of a novel therapy for asthma (bronchial thermoplasty) that utilizes thermal energy to disrupt airway smooth muscle and presented study data to the FDA Medical Advisory panel in 2009, leading to its 2010 FDA approval. I was also awarded an NIH sponsored R21 award to examine the effects of placebo on lung function in asthma, and completed this clinical trial work in over 40 subjects. Having reported on the importance of using placebos in clinical trials and on the relevance of patient reported outcomes in clinical trials, my NEJM manuscript has reset the standard for clinical trial design in this condition. I am a member of the Steering Committee of the NIH-sponsored Asthma Clinical Research Network (ACRN, now called Asthmanet), a multi-center asthma clinical trials consortium that has conducted numerous trials that have clarified our understanding of asthma phenotyping and asthma management, laying the foundation for current asthma guidelines. As a member of this consortium, I was the lead investigator who described an association between asthma treatment failures and beta agonist use in African Americans , and am a lead investigator in 2 seprate trials examining race-specific differences in response to asthma therapy.
A major focus of my research efforts is elucidating the pathophysiology of the Churg-Strauss syndrome, a rare form of eosinophilic vasculitis. I was the first to describe the relationship between CSS and leukotriene modifiers, and between CSS and anti-IgE therapy for asthma . I clinically follow one of the largest cohorts of CSS patients in the country and I serve as a referral base for patients with severe asthma from all over the USA. This expertise, and two research awards, have enabled me to recruit the largest cohort of CSS patients, which are serving as the primary test population in a genome-wide association study of CSS. I have examined the role of anti-IL5 in the treatment of CSS patients and have received NIAID R34 funding to plan a double blind placebo controlled trial in this patient population, that is set to start in 2013.
Wechsler ME, Kunselman SJ, Chinchilli VM, Bleecker E, Boushey HA, Calhoun WJ, Ameredes BT, Castro M, Craig TJ, Denlinger L, Fahy JV, Jarjour N, Kazani S, Kim S, Kraft M, Lazarus SC, Lemanske Jr RF, Markezich A, Martin RJ, Permaul P, Peters SP, Ramsdell J, Sorkness CA, Sutherland ER, Szefler SJ, Walter MJ, Wasserman S, Israel E. Effect of beta2-adrenergic receptor polymorphism on response to long acting beta2 agonist in asthma (LARGE trial): a genotype-stratified, randomized, placebo-controlled, crossover trial. The Lancet. 2009; 374(9703):1754-64. (PMCID: PMC2914569)
This prospective clinical trial followed up the retrospective data noted above examining pharmacogenetic effects of beta receptor gene polymorphisms on response to salmeterol. While peak flow did not differ between individuals of different genotypes when treated with salmeterol, B16Arg-Arg patients gained no benefit by adding salmeterol with respect to methacholine responsiveness. Furthermore, B16Arg-Arg African-Americans failed to improve lung function with addition of salmeterol, possibly modifying the risk-benefit ratio of salmeterol in this population. These findings again highlighted the potential importance of pharmacogenetics in asthma.
Castro M, Rubin AS, Laviolette M, Fiterman J, Lima M, Shah PL, Fiss E, Olivenstein R, Thomson NC, Niven RM, Pavord ID, Simoff M, Duhamel DR, McEvoy C, Barbers R, ten Hacken NHT, Wechsler ME, Holmes M, Phillips MJ, Erzurum S, Lunn W, Israel E, Jarjour N, Kraft M, Berry SM, Quiring J, Shargill NS, Cox G. Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: A multicenter, randomized, double-blinded, sham-controlled clinical trial. Am. J. Respir. Crit. Care Med. 2010; 181(2):116-24 (PMCID: PMC2914569)
Bronchial thermoplasty (BT) is a bronchoscopic procedure in which controlled thermal energy is applied to the airway wall to decrease smooth muscle. In this pivotal trial, we demonstrated that in subjects with severe asthma, bronchial thermoplasty improves asthma-specific quality of life with a reduction in severe exacerbations and healthcare use after one year of therapy. As one of the highest investigator enrollers for this trial in the US, I personally performed this procedure on one of the largest volumes of patients in the trial, and supported the procedure’s approval at the FDA. I have also taken the lead on the recently submitted analysis of 5 year safety and efficacy data of BT.
Kim S, Oren E, Marigowda G, Israel E, Wechsler ME. Mepolizumab as a steroid sparing agent in Churg-Strauss syndrome. J Allergy Clin Immunol 2010; 125(6):1336-43 (PMCID: PMC2964431).
As treatment options for CSS are often limited by safety and efficacy, we sought to assess whether Mepolizumab, an anti–IL-5 antibody, could decrease steroid requirements in patients with non-CSS hypereosinophilic syndromes. We demonstrated that mepolizumab was safe and well tolerated in patients with CSS, reduced eosinophil counts, and allowed for safe corticosteroid reduction in all subjects. This study has paved the way for my R34 and U01 grants that involve a double blind placebo controlled trial of mepolizumab in CSS, that will also examine several pathophysiologic and genetic aspects of CSS.
Wechsler ME, Kelley JM, Boyd IOE, Dutile S, Marigowda G, Kirsch I, Israel E Kaptchuk TJ. Active or Placebo Albuterol, Sham Acupuncture or No Treatment in Asthma. New Engl J Med 2011 365(2):119-126. (PMID: 21751905)
In this NIH R21 funded, double blind controlled trial, we compared the effects of a bronchodilator , two placebo interventions, and no intervention on outcomes in patients with asthma. Although albuterol, but not the two placebo interventions, improved FEV1 in these patients with asthma, albuterol provided no incremental benefit with respect to the self-reported outcomes. This study had a significant impact on asthma clinical trials, as we concluded that placebo effects can be clinically meaningful and can rival the effects of active medication in patients with asthma, while from a clinical management and research-design perspective, patient self-reports can be unreliable. Thus, an assessment of untreated responses in asthma may be essential in evaluating patient-reported outcomes.
Wechsler ME, Castro M, Lehman E, Chinchilli V, Rand Sutherland E, Denlinger L, Lazarus SC, Peters SP, Israel E, the NHLBI Asthma Clinical Research Network. Impact of race on asthma treatment failures in the Asthma Clinical Research Network. Am J Respir Crit Care Med 2011 184:1247-1253. (PMID: 21885625)
In this retrospective analysis of clinical trials of adult asthmatics in which individuals were provided access to clinicians and medications, and in which subjects were monitored for medication adherence, we demonstrated that African Americans experienced higher rates of asthma treatment failures than Caucasians, especially when taking long-acting beta-agonists, despite having fewer symptoms and less rescue beta-agonist use. This study has paved the way for a large multicenter AHRQ funded clinical trial examining the relative effect of different asthma therapies in Blacks, as well as my leadership of a large NHLBI Asthmanet study examining effects of inhaled corticosteroids in Black adults and children with asthma.