Merritt L. Fajt

Prostaglandin D2 pathway upregulation: Relation to asthma severity, control, and TH2 inflammation

BACKGROUND Bronchoalveolar lavage (BAL) fluid prostaglandin D₂(PGD₂) levels are increased in patients with severe, poorly controlled asthma in association with epithelial mast cells (MCs). PGD₂, which is generated by hematopoietic prostaglandin D synthase (HPGDS), acts on 3 G protein-coupled receptors, including chemoattractant receptor-homologous molecule expressed on TH2 lymphocytes (CRTH2) and PGD₂ receptor 1 (DP1). However, much remains to be understood regarding the presence and activation of these pathway elements in asthmatic patients. OBJECTIVE We sought to compare the expression and activation of PGD₂ pathway elements in bronchoscopically obtained samples from healthy control subjects and asthmatic patients across a range of disease severity and control, as well as in relation to TH2 pathway elements. METHODS Epithelial cells and BAL fluid were evaluated for HPGDS (quantitative real-time PCR/immunohistochemistry [IHC]) and PGD₂ (ELISA/liquid chromatography mass spectrometry) in relation to levels of MC proteases. Expression of the 2 inflammatory cell receptors DP1 and CRTH2 was evaluated on luminal cells. These PGD₂ pathway markers were then compared with asthma severity, level of control, and markers of TH2 inflammation (blood eosinophils and fraction of exhaled nitric oxide). RESULTS Confirming previous results, BAL fluid PGD₂ levels were highest in patients with severe asthma (overall P = .0001). Epithelial cell compartment HPGDS mRNA and IHC values differed among groups (P = .008 and P < .0001, respectively) and correlated with MC protease mRNA. CRTH2 mRNA and IHC values were highest in patients with severe asthma (P = .001 and P = .0001, respectively). Asthma exacerbations, poor asthma control, and TH2 inflammatory markers were associated with higher PGD₂, HPGDS, and CRTH2 levels. CONCLUSION The current study identifies coordinated upregulation of the PGD₂ pathway in patients with severe, poorly controlled, TH2-high asthma despite corticosteroid use.

Inflammatory and Comorbid Features of Patients with Severe Asthma and Frequent Exacerbations

Rationale: Reducing asthma exacerbation frequency is an important criterion for approval of asthma therapies, but the clinical features of exacerbation‐prone asthma (EPA) remain incompletely defined. Objectives: To describe the clinical, physiologic, inflammatory, and comorbidity factors associated with EPA. Methods: Baseline data from the NHLBI Severe Asthma Research Program (SARP)‐3 were analyzed. An exacerbation was defined as a burst of systemic corticosteroids lasting 3 days or more. Patients were classified by their number of exacerbations in the past year: none, few (one to two), or exacerbation prone (≥3). Replication of a multivariable model was performed with data from the SARP‐1 + 2 cohort. Measurements and Main Results: Of 709 subjects in the SARP‐3 cohort, 294 (41%) had no exacerbations and 173 (24%) were exacerbation prone in the prior year. Several factors normally associated with severity (asthma duration, age, sex, race, and socioeconomic status) did not associate with exacerbation frequency in SARP‐3; bronchodilator responsiveness also discriminated exacerbation proneness from asthma severity. In the SARP‐3 multivariable model, blood eosinophils, body mass index, and bronchodilator responsiveness were positively associated with exacerbation frequency (rate ratios [95% confidence interval], 1.6 [1.2‐2.1] for every log unit of eosinophils, 1.3 [1.1‐1.4] for every 10 body mass index units, and 1.2 [1.1‐1.4] for every 10% increase in bronchodilatory responsiveness). Chronic sinusitis and gastroesophageal reflux were also associated with exacerbation frequency (1.7 [1.4‐2.1] and 1.6 [1.3‐2.0]), even after adjustment for multiple factors. These effects were replicated in the SARP‐1 + 2 multivariable model. Conclusions: EPA may be a distinct susceptibility phenotype with implications for the targeting of exacerbation prevention strategies. Clinical trial registered with www.clinicaltrials.gov (NCT 01760915).

Development of New Therapies for Severe Asthma

Persistent asthma has long been treated with inhaled corticosteroids (CSs), as the mainstay of therapy. However, their efficacy in patients with more severe disease is limited, which led to the incorporation of poor response to ICSs (and thereby use of high doses of ICS) into recent definitions of severe asthma. Several studies have suggested that severe asthma might consist of several different phenotypes, each with ongoing symptoms and health care utilization, despite the use of high doses of ICS, usually in combination with a second or third controller. Several new therapies have been approved for severe asthma. Long-acting muscarinic agents have recently been approved as an additional controller agent and appear to improve lung function, although their effect on symptoms and exacerbations is less. Although bronchial thermoplasty (BT) has emerged as a therapy for severe asthma, little is understood regarding the appropriate selection of these patients. Considerable data have emerged to support the presence of a group of patients with severe asthma who have ongoing Type 2 inflammation. These patients appear to respond to targeted biologic approaches which are at the current time mostly investigational. In contrast, few effective therapies for patients with less or no evidence for Type 2 inflammation have emerged. Many new and exciting therapies are at the forefront for severe asthma therapy and, in conjunction with precision medicine approaches to identify the group of patients likely to respond to these approaches, will change the way we think about treating severe asthma.

A Novel Scoring System to Distinguish Vocal Cord Dysfunction From Asthma

BACKGROUND Vocal cord dysfunction is often misdiagnosed and mistreated as asthma, which can lead to increased and unnecessary medication use and increased health care utilization. OBJECTIVE To develop a valid scoring index that could help distinguish vocal cord dysfunction from asthma. METHODS We compared the demographics, comorbidities, clinical symptoms, and symptom triggers of subjects with vocal cord dysfunction (n = 89) and those with asthma (n = 59). By using multivariable logistic regression, we identified distinguishing features associated with vocal cord dysfunction, which were weighted and used to generate a novel score. The scoring index also was tested in an independent sample with documented vocal cord dysfunction (n = 72). RESULTS We identified symptoms of throat tightness and dysphonia, the absence of wheezing, and the presence of odors as a symptom trigger as key features of vocal cord dysfunction that distinguish it from asthma. We developed a weighted index based on these characteristics, the Pittsburgh Vocal Cord Dysfunction Index. By using a cutoff of ≥4, this index had good sensitivity (0.83) and specificity (0.95) for the diagnosis of vocal cord dysfunction. The scoring index also performed reasonably well in the independent convenience sample with laryngoscopy-proven vocal cord dysfunction and accurately made the diagnosis in 77.8% of subjects. CONCLUSION The Pittsburgh Vocal Cord Dysfunction Index is proposed as a simple, valid, and easy-to-use tool for diagnosing vocal cord dysfunction. If confirmed by a prospective evaluation in broader use, it may have significant clinical utility by facilitating a timely and accurate diagnosis of vocal cord dysfunction, thereby preventing misdiagnosis and mistreatment as asthma. Future prospective validation studies will need to be performed.

Effects of Age and Disease Severity on Systemic Corticosteroid Responses in Asthma

Rationale: Phenotypic distinctions between severe asthma (SA) and nonsevere asthma (NONSA) may be confounded by differential adherence or incorrect use of corticosteroids. Objectives: To determine if there are persistent phenotypic distinctions between SA (as defined by 2014 American Thoracic Society/European Respiratory Society guidelines) and NONSA after intramuscular triamcinolone acetonide (TA), and to identify predictors of a corticosteroid response in these populations. Methods: A total of 526 adults age 18 years and older (315 SA) and 188 children age 6 to less than 18 years (107 SA) in the NHLBI Severe Asthma Research Program III were characterized before and 3 weeks after TA. The primary outcome for corticosteroid response was defined as greater than or equal to 10‐point improvement in percent predicted FEV1. Measurements and Main Results: Adult asthma groups exhibited a small but significant mean FEV1% predicted improvement after TA (SA group mean difference, 3.4%; 95% confidence interval, 2.2‐4.7%; P = 0.001), whereas children did not. Adult SA continued to manifest lower FEV1 and worse asthma control as compared with NONSA after TA. In children, after TA only prebronchodilator FEV1 distinguished SA from NONSA. A total of 21% of adults with SA and 20% of children with SA achieved greater than or equal to 10% improvement after TA. Baseline bronchodilator response and fractional exhaled nitric oxide had good sensitivity and specificity for predicting response in all groups except children with NONSA. Conclusions: One in five patients with SA exhibit greater than or equal to 10% improvement in FEV1 with parenteral corticosteroid. Those likely to respond had greater bronchodilator responsiveness and fractional exhaled nitric oxide levels. In adults, differences in airflow obstruction and symptoms between SA and NONSA persist after parenteral corticosteroids, suggesting a component of corticosteroid nonresponsive pathobiology in adults with SA that may differ in children. Clinical trial registered with www.clinicaltrials.gov (NCT 01606826).

Biologic therapy in asthma: entering the new age of personalized medicine

Abstract Objective: Asthma is a common chronic disease with various phenotypes and therapeutic responses. Unlike other diseases, current anti-inflammatory treatment with corticosteroids does not include any reference to biological measures which may vary among different asthma phenotypes. Morbidity from uncontrolled asthma suggests a need for specific targeted treatment approaches such as biologic medications. In half of asthmatics, chronic airway inflammation may be driven by T helper (Th)-2 cells, which release pro-inflammatory cytokines, such as interleukin (IL)-4, IL-5 and IL-13, contributing to eosinophil inflammation and IgE production. Earlier studies of cytokine-targeted biologic therapy on non-phenotyped asthma patients were generally not clinically effective. Methods: Literature published from 1958–2013 was identified through PubMed using the search terms which included asthma and therapy. A total of 32 studies were reviewed covering both pediatric and adult asthmatics and included double-blind randomized placebo-controlled trials testing efficacy of biologic agents to treat asthma. Results: More recent approaches to personalized medicine with expression profiling studies, genetic analysis and clinical biomarkers of Th2 inflammation have allowed identification of asthma phenotypes including a Th2 “high” phenotype. Studies targeting IgE, IL-5, IL-13 and the IL4 receptor alpha chain have shown some efficacy in phenotyped patients. For those without evidence of Th2 inflammation, no specific therapies have been identified. Conclusions: In recent years, the identification of Type-2 cytokine “high” asthma in numerous studies has predicted the clinical response to the Th2 associated therapies. It is not yet clear whether all Type 2 high asthma will respond similarly to IL-4, 5 and 13 approaches.

Asthma phenotypes in adults and clinical implications

It is becoming increasingly recognized that asthma is a heterogeneous disease, whether based on clinical factors, including the patient’s age at diagnosis, symptom spectrum and treatment response, triggering factors, or the level and type of inflammation. Attempts to analyze the importance of these characteristics to the clinical presentation of asthma have led to the appreciation of numerous separate and overlapping asthma phenotypes. However, these approaches are ‘biased’ and based on the clinician/scientist’s own experience. Recently, unbiased approaches have also been attempted using both molecular and statistical tools. Early results from these approaches have supported and expanded on the clinician’s concepts. However, until specific biologic markers are identified for any of these proposed phenotypes, the definitive nature of any phenotype will remain speculative.

The morbidity and cost of vocal cord dysfunction misdiagnosed as asthma.

BACKGROUND Vocal cord dysfunction (VCD) is frequently misdiagnosed and mistreated as asthma, which leads to morbidity secondary to unnecessary medication use and increased health care utilization. OBJECTIVE We identified discriminating symptoms and triggers, and analyzed the costs, morbidity, and health care burden associated with misdiagnosis of VCD as asthma. We sought to determine if current measures of asthma control contributed to these findings. We evaluated if a simple set of breathing exercises would be an effective low-cost treatment option for those with VCD. METHODS We compared the demographics, comorbidities, clinical symptoms, and symptom triggers of subjects with VCD misdiagnosed as asthma compared with those not misdiagnosed as asthma. Costs secondary to asthma misdiagnosis were quantified, and the effectiveness of breathing exercises as a treatment option was evaluated. RESULTS We identified symptoms of shortness of breath, wheezing, chest tightness, and a trigger of exercise as being more common in the subjects with VCD misdiagnosed as asthma. Asthma medication use and health care utilization and costs were also higher in this group. The subjects with VCD had Asthma Control Questionnaire scores that labelled them as having uncontrolled asthma. Breathing exercises appeared to offer an inexpensive and effective treatment option for subjects with VCD. CONCLUSION Misdiagnosis of VCD as asthma leads to significant morbidity and increased costs, and misuse of measures of asthma control may be contributing to these findings. Timely and accurate diagnosis of VCD and the use of breathing exercises have the potential to eliminate or minimize the burdens on the patient and the health care system.

Clopidogrel Hypersensitivity: A Novel Multi-Day Outpatient Oral Desensitization Regimen

BACKGROUND Clopidogrel hypersensitivity has posed a problem for the acute treatment and long-term care of a particular patient population with coronary artery disease and stent placement. Patients with clopidogrel hypersensitivity have had an increased risk of hypersensitivity reactions, including anaphylaxis, if they ingest clopidogrel without undergoing an oral desensitization procedure. The previously published desensitization protocols have either been performed in the intensive care unit, requiring significant cost and healthcare utilization, or have required a full-day outpatient commitment on behalf of the patient. OBJECTIVE To determine whether a multi-day outpatient oral clopidogrel desensitization protocol is effective and safe for patients with clopidogrel hypersensitivity. METHODS gWe retrospectively assessed the efficacy of a 10-dose outpatient multiday clopidogrel desensitization protocol performed in a university allergy-immunology center from April 2006 to October 2008 in patients with clopidogrel hypersensitivity. Patients were desensitized over 2–3 half-day clinical visits and were able to go home between desensitization sessions. A preliminary cost analysis was performed using the average of actual costs for the outpatient clopidogrel desensitization procedure and was compared with the average cost for an inpatient oral desensitization completed at our institution. RESULTS Eight patients with coronary artery disease, cardiac stent placement, and clopidogrel hypersensitivity underwent an outpatient multi-day oral clopidogrel desensitization procedure. All patients were successfully desensitized with the multi-day protocol without complications. No patient had recurrence of allergic reaction 3 months after the procedure. A preliminary cost analysis demonstrated a lower cost for the outpatient compared to the inpatient oral clopidogrel desensitization protocol. CONCLUSIONS This outpatient 10-dose multi-day clopidogrel desensitization protocol is a safe and effective novel approach for the treatment of clopidogrel hypersensitivity in patients with coronary artery disease and cardiac stent placement. In addition to safety and efficacy, this protocol offers the patient the convenience of avoiding hospital admission or full-day time commitments.

Natural killer cell–mediated inflammation resolution is disabled in severe asthma

Severe asthma is characterized by decreased NK cell cytotoxicity, and corticosteroids further disable NK cell function. NK cells in severe asthma—Failed resolution Anti-inflammatory corticosteroids are a first line of defense against many types of asthma, but patients with severe asthma do not frequently respond to this therapy. Duvall et al. now report that this lack of response may be due in part to defects in natural killer (NK) cells, which are important mediators of inflammation resolution. They found that NK cells from patients with severe asthma had impaired killing and that corticosteroid exposure further inhibited the function of these cells, whereas the proresolving mediator LXA4 preserved NK cell effector mechanisms. Therefore, corticosteroids may be a counterproductive therapy in patients with severe asthma, and specifically activating NK cells may provide an alternate therapeutic target. Severe asthma is typically characterized by chronic airway inflammation that is refractory to corticosteroids and associated with excess morbidity. Patients were recruited into the National Heart, Lung, and Blood Institute–sponsored Severe Asthma Research Program and comprehensively phenotyped by bronchoscopy. Bronchoalveolar lavage (BAL) cells were analyzed by flow cytometry. Compared with healthy individuals (n = 21), patients with asthma (n = 53) had fewer BAL natural killer (NK) cells. Patients with severe asthma (n = 29) had a marked increase in the ratios of CD4+ T cells to NK cells and neutrophils to NK cells. BAL NK cells in severe asthma were skewed toward the cytotoxic CD56dim subset, with significantly increased BAL fluid levels of the cytotoxic mediator granzyme A. The numbers of BAL CD56dim NK cells and CCR6−CCR4− T helper 1–enriched CD4+ T cells correlated inversely with lung function [forced expiratory volume in 1 s (FEV1) % predicted] in asthma. Relative to cells from healthy controls, peripheral blood NK cells from asthmatic patients had impaired killing of K562 myeloid target cells despite releasing more cytotoxic mediators. Ex vivo exposure to dexamethasone markedly decreased blood NK cell lysis of target cells and cytotoxic mediator release. NK cells expressed airway lipoxin A4/formyl peptide receptor 2 receptors, and in contrast to dexamethasone, lipoxin A4–exposed NK cells had preserved functional responses. Together, our findings indicate that the immunology of the severe asthma airway is characterized by decreased NK cell cytotoxicity with increased numbers of target leukocytes, which is exacerbated by corticosteroids that further disable NK cell function. These failed resolution mechanisms likely contribute to persistent airway inflammation in severe asthma.