Traditionally, asthma and allergic diseases have been defined by broad definitions and treated with nonspecific medications, including corticosteroids and bronchodilators. There is an increasing ...appreciation of heterogeneity within asthma and allergic diseases based primarily on recent cluster analyses, molecular phenotyping, biomarkers, and differential responses to targeted and nontargeted therapies. These pioneering studies have led to successful therapeutic trials of molecularly targeted therapies in defined phenotypes. This review analyzed randomized double-blind, placebo-controlled trials of molecularly targeted therapies in defined allergic disease and asthma phenotypes. IgE was the first successful biological target used in patients with allergic disease and asthma. This review shows that therapies targeting the canonical type 2 cytokines IL-4, IL-5, and IL-13 have shown consistent efficacy, especially in asthmatic patients with evidence of TH 2/type 2 inflammation (“type 2 high”). As of yet, there are no successful trials of targeted therapies in asthmatic patients without evidence for type 2 inflammation. We conclude that further refinement of type 2 therapies to specific type 2 phenotypes and novel approaches for patients without type 2 inflammation are needed for asthma and allergic disease treatment.
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.
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.
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.
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).
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.
The current study identifies coordinated upregulation of the PGD2 pathway in patients with severe, poorly controlled, TH2-high asthma despite corticosteroid use.
Vocal cord dysfunction is often misdiagnosed and mistreated as asthma, which can lead to increased and unnecessary medication use and increased health care utilization.
To develop a valid scoring ...index that could help distinguish vocal cord dysfunction from asthma.
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).
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.
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.
Bile acid profiles are altered in obese individuals with asthma. Thus, we sought to better understand how obesity-related systemic changes contribute to lung pathophysiology. We also test the ...therapeutic potential of nitro-oleic acid (NO
-OA), a regulator of metabolic and inflammatory signaling pathways, to mitigate allergen and obesity-induced lung function decline in a murine model of asthma. Bile acids were measured in the plasma of healthy subjects and individuals with asthma and serum and lung tissue of mice with and without allergic airway disease (AAD). Lung function, indices of inflammation and hepatic bile acid enzyme expression were measured in obese mice with house dust mite-induced AAD treated with vehicle or NO
-OA. Serum levels of glycocholic acid and glycoursodeoxycholic acid clinically correlate with body mass index and airway hyperreactivity whereas murine levels of β-muricholic acid and tauro-β-muricholic acid were significantly increased and positively correlated with impaired lung function in obese mice with AAD. NO
-OA reduced murine bile acid levels by modulating hepatic expression of bile acid synthesis enzymes, with a concomitant reduction in small airway resistance and tissue elastance. Bile acids correlate to body mass index and lung function decline and the signaling actions of nitroalkenes can limit AAD by modulating bile acid metabolism, revealing a potential pharmacologic approach to improving the current standard of care.
Methods We conducted a retrospective chart review of 430 adult patients seen in an Adult University Allergy clinic who started AIT for treatment of allergic rhinoconjunctivitis from June 15, 2004 ...through June 15, 2014.
Worldwide, iron deficiency anemia is the most common nutritional disorder. Treatment with oral iron supplementation may not be well tolerated due to gastrointestinal side effects. Therapy with ...Intravenous (IV) iron supplementation is more effective and better tolerated, especially in patients with underlying Inflammatory Bowel Disease (IBD) or malignancy. However, Hypersensitivity Reactions (HSR) and anaphylaxis to IV iron have been described.
We evaluated the literature and developed an eleven step desensitization protocol for ferric carboxymaltose to be administered in high risk patients.
We present the first case series demonstrating the safety of ferric carboxymaltose desensitization in patients with a history of anaphylaxis to IV iron and iron deficiency anemia.
While there are many IV iron formulations available, ferric carboxymaltose can replenish iron stores with fewer doses. Ferric carboxymaltose is contraindicated in patients with prior hypersensitivity reactions to iron formulations. This novel eleven step desensitization protocol was well tolerated without any adverse reactions and allowed the patients to receive iron supplementation when limited therapeutic options existed.
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