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Tuesday, April 14, 2015

Biomarker-based asthma phenotypes of corticosteroid response

Inhaled corticosteroids (ICSs) are the mainstay of treatment of asthma. However, a considerable proportion of asthmatic patients do not respond to ICSs based on lung function, or other clinical outcomes, or both. Therefore, biomarkers relevant to the underlying pathophysiologic process, the response to treatment, or both would be useful in personalizing care of asthmatic patients. This need led Cowan et al to follow up from an original study of a 2 phase trial consisting of a steroid-naïve phase 1 and a 28-day trial of ICSs (phase 2) during which fraction of exhaled nitric oxide (FENO) values, eosinophil counts, and urinary bromotyrosine (BrTyr) levels were measured in asthmatic patients (J Allergy Clin Immunol 2015; 135(4): 877-883).

Over the last decade, FENO values and sputum eosinophil counts have been used as biomarkers of airway inflammation and predictors of steroid responsiveness. FENO values are correlated with airway eosinophilia and associated with airway hyper-responsiveness. Moreover, studies indicate that high FENO values in asthmatic patients indicate an at-risk phenotype for exacerbations and predict clinical response to ICSs or oral corticosteroids. Eosinophils are well recognized as biomarkers of active atopic inflammation and a relationship exists between sputum eosinophil counts and exacerbation of withdrawal of steroids. Upon activation, eosinophils undergo respiratory burst, generating high levels of reactive oxygen species and eosinophil peroxidase that is unique in its ability to convert respiratory burst-generated hydrogen peroxide into hypobromous acid, a reactive brominating oxidant that modifies protein tyrosine residues forming urinary BrTyr.

The authors compared the utility of a panel of biomarkers consisting of FENO, sputum eosinophils, and urine BrTyr that identify the presence of atopic inflammation and oxidative stress for prediction of clinical response to steroids. They show that the effect of ICSs on inflammatory biomarkers was not uniformly concordant, although there were substantial parallel decreases among biomarkers. Each of the biomarkers had utility for predicting steroid responsiveness; the combination of high FENO values and high urinary BrTyr levels had particular power to predict a favorable clinical response to ICS therapy with either improvement in Asthma Control Questionnaire score, FEV1 or airway reactivity. Cowan concludes that future studies must focus on evaluation of biomarker panels for assessment of exacerbation risk and whether the magnitude of change in biomarker values might predict the magnitude of clinical benefit with treatments.

Question for the authors:
Do you see other applications for this biomarker panel for the clinical benefit of asthma, such as aiding in the determination of asthma subtypes early in diagnosis?

Response from the authors:

Our study highlights the potential for utilizing the combination of urinary Br Tyr and FENO to predict the likelihood of steroid responsiveness in asthmatic individuals, without resorting to sputum induction, preparation and analysis.  These measurements could be made at the first clinic visit so that treatment can be tailored to the individual allowing steroids to be prescribed in a targeted fashion whilst also allowing the earlier consideration of other treatments in non-steroid responsive asthma subtypes.  Further studies should focus on the identification of alternative treatments in these steroid-unresponsive phenotypes.

Friday, April 10, 2015

Overweight children report qualitatively distinct asthma symptoms: Analysis of validated symptom measures

The relationship between overweight/obesity and asthma phenotype in children remains inadequately defined. Several large epidemiologic studies have demonstrated that obesity increases the risk of physician-diagnosed asthma and is associated with greater asthma-related health utilization and asthma that is more problematic and difficult to control. This discrepancy regarding the impact of obesity suggests that more in-depth and novel assessments of lean and obese asthmatic children may be required. Specifically, few studies have addressed how obese patients perceive and report asthma symptoms. This led Lang et al to determine the qualitative differences in symptoms between lean and overweight/obese children with early-onset, atopic asthma (J Allergy Clin Immunol 2015; 135(4): 886-893).

The authors conducted a cross-sectional analytic study of lean and overweight/obese 10-17 year old children with persistent, early-onset asthma. Participants provided a complete history, qualitative and quantitative asthma symptom characterization, and lung function testing. They determined associations between weight status and symptoms using multivariable linear and logistic regression methods. The authors report that overweight/obese and lean children displayed similar baseline spirometry values. However, despite lower fraction of exhaled nitric oxide and reduced methacholine responsiveness, overweight/obese children reported requiring rescue treatments more than 3x that of lean children. Weight status affected the child’s primary symptom reported with loss of asthma control; overweight/obese children more often reported shortness of breath and less often reported cough.   Using three validated questionnaires for assessing asthma symptom control, the authors showed that overweight/obese status was consistently associated with greater symptom reporting.  Subscale analysis suggested that shortness of breath and self-medication with rescue medication consistently drove the worse asthma scoring.  Gastroesophageal reflux (GER) scores were higher in overweight/obese children and appear to mediate overweight/obesity-related asthma symptoms.

Lang concludes that overweight/obese children with early-onset asthma display poorer asthma control and a distinct pattern of symptoms. Moreover, greater shortness of breath and β-agonist use appears to be partially mediated via esophageal reflux symptoms, which may lead to overweight children with asthma falsely attributing exertional dyspnea and esophageal reflux to asthma and excess rescue medication use. Because dyspnea from asthma is a major driver of anxiety, reduced quality of life, health care utilization, and medication use, a greater understanding of the distinct sensory mechanisms of dyspnea is needed. Until systematic weight loss interventions become more feasible, respiratory physicians may serve their patients better by considering and discussing alternative causes of dyspnea in self-management plans.

Question for the authors:
Are there other factors associated with obesity that may be a factor in the severity of asthma symptoms, such as socioeconomic and health related factors?

Several comorbidities associated with obesity are also likely to influence asthma either directly or by complicating its perception and management.  The best examples include snoring/sleep apnea, immune and metabolic derangements and impaired cardiopulmonary reserve.  We adjusted for presence of snoring in our analysis which did not affect our results (as did adjusting for GER scores).  Lower socioeconomic status has been associated in the past with greater prevalence of obesity and worse asthma control, thereby making it a possible confounding factor.  However, several socioeconomic and environmental factors were measured in our study including race, ethnicity, parental education, income, inutero smoking and later environmental smoke exposure.  None of these measures were associated with overweight/obesity status in our study.  We did not measure for levels of activity.  The effect of daily activity on disease activity, response to controller therapy, and perception of asthma symptoms requires more investigation and may provide important insights into the relationship between obesity and asthma.  

Wednesday, April 8, 2015

The prevalence of severe refractory asthma

Severe asthma is characterized by difficulty to achieve disease control despite high-dose inhaled glucocorticoids plus long acting β2 –agonists (LABAs) or oral corticosteroids (OCSs). In 2011, the Innovative Medicine Initiative (IMI) published an international consensus statement in which a more accurate definition of severe asthma was proposed. In this statement, a clear distinction was made between “difficult to control asthma” and “severe refractory asthma.” In patients with difficult to control asthma, the lack of asthma control is due to other factors than asthma itself, such as nonadherence to treatment or incorrect inhalation technique. On the other hand, in patients with severe refractory asthma, the disease remains uncontrolled despite addressing and removing all possible factors that might aggravate the underlying disease. Hekking et al sought to estimate the prevalence of severe refractory asthma as defined by the IMI consensus (J Allergy Clin Immunol 2015; 135(4): 896-902).

Adult patients with a prescription for high-intensity treatment were extracted from 65 Dutch pharmacy databases, representing 3% of the population. Questionnaires were sent to patients and about half (2312) were analyzed. The diagnosis of asthma and degree of asthma control were derived from the questionnaires to identify patients with difficult-to-control asthma and inhalation technique was assessed in a random sample of 60 adherent patients. The authors determined that patients with difficult to control asthma, adherence to treatment, and a correct inhalation technique were qualified as having severe refractory asthma. The results indicated that of asthmatic adults, 3.6% qualified for a diagnosis of severe refractory asthma, representing 10.4 patients per 10,000 inhabitants.

The authors speculate about the reasons for the difference between the prevalence of severe refractory asthma mentioned in the literature (5%-10%) and their results (3.6%). Estimations in the literature are based on expert opinion and clinical experience, it is reasonable to believe that not all factors that negatively influence asthma control are receiving full attention in the consulting room. Therefore clinical overestimation of the prevalence of truly severe refractory asthma might easily occur because of misclassification of patients with difficult-to-control asthma as patients with severe refractory asthma. Clinicians should be aware of the distinction between these 2 conditions and check potential aggravating factors, in particular poor adherence with treatment and inadequate inhalation technique. Another important result of this study is because the prevalence of this condition might be lower than previously thought, severe refractory asthma could fulfill the criteria of a rare disease and qualifies for niche drugs. Together, these data will hopefully facilitate the development and reimbursement of novel targeted treatments. 

Wednesday, March 18, 2015

Pioglitazone restores mitochondrial oxidant production in CGD phagocytes and enhances their bactericidal capacity

In addition to having a nonfunctional NADPH oxidase, activated phagocytes from patients with chronic granulomatous disease (CGD) and gp91phox-/- mice (modeling X-linked CGD) lack oxidant production from mitochondria, as reported by authors Fernandez-Boyanapalli et al ( . Specifically, neutrophils and monocytes from blood, as well as recruited neutrophils and macrophages from inflamed tissues of CGD mice, failed to produce mitochondrial oxidants when activated. Deficient mitochondrial oxidant production was shown to contribute to impaired bactericidal activity against Staphylococcus aureus and Burkholderia cepacia in vitro. Importantly, the researchers demonstrated that mitochondrial oxidant production was restored (see Figure) following short-term treatment of CGD mice with pioglitazone, a PPAR? agonist approved for treatment of type 2 diabetes. Pioglitazone is known to induce metabolic changes that mimic “starvation signaling,” including altering mitochondrial functions. Treatment of CGD mice with pioglitazone restored the bactericidal activity of their phagocytes to approximately 30% of normal murine phagocytes and enhanced early bacterial clearance of S aureus in a peritonitis model. Treatment of monocytes from X-linked CGD patients with pioglitazone ex vivo similarly restored mitochondrial oxidant production supporting the hypothesis that pioglitazone may be useful therapeutically in the treatment of CGD.

Tuesday, March 17, 2015

Anti-IL-23A mAb BI 655066 for treatment of moderate-to-severe psoriasis: Safety, efficacy, pharmacokinetics, and biomarker results of a single-rising-dose, randomized, double-blind, placebo-controlled trial

Psoriasis, a chronic immune-mediated inflammatory skin disease, affects approximately 2% of the global population. Eighty to ninety percent of patients have plaque psoriasis, and the extent of the affected surface areas of the body and the degree of redness, hardening, and scaling of the skin define its severity. In addition to its negative effect on well-being and quality of life, moderate-to-severe psoriasis has comorbidities including increased risk of heart disease and stroke. Approximately 25% of psoriasis patients have moderate-to-severe disease.

Genome-wide association studies have previously linked a variant in the genes for the IL-23 receptor and the p19 subunit of IL-23, or IL-23A, to psoriasis susceptibility. BI 655066 is a fully-human IgG1 mAb selective for IL-23A. In this phase I proof-of-concept study, Krueger et al evaluated the results of administering a single-rising-dose of BI 655066 to patients with moderate-to-severe plaque psoriasis (J Allergy Clin Immunol 2015, in press). The primary objective was to assess the safety and tolerability of BI 65066, which was done via physical examinations, vital signs, electrocardiogram, clinical laboratory tests, and occurrence of adverse events.  However, mechanistic effects of IL-23 blockade were explored by histologic methods, deep RNA sequencing, and quantitative RT-PCR methods.

The study, the first of its kind, found that the majority of patients well-tolerated single-dose BI 655066. The patients who received the antibody showed clinical improvement after 2 weeks that was maintained for up to 66 weeks after treatment. After 12 weeks, 87% of treated patients experienced a decrease in  the Psoriasis Area and Severity Index of  at least 75% (PASI75). The treatment and placebo groups reported a similar frequency of adverse events. Strong inhibition of IL-17 and disease-related genes related to the IL-23/Th17 axis was measured in antibody-treated patients.  Treatment responses were maintained in most patients until 24 weeks and a smaller subset of patients followed without additional treatment maintained clearing of psoriasis for 10 months or more.  The results support a new model for treating psoriasis and raise the possibility of attaining long-term remission from a single drug intervention.

Monday, March 9, 2015

Allergy to furry animals: New insights, diagnostic approaches, and challenges

The prevalence of allergy to furry animals has been increasing, and allergy to cats, dogs, or both is considered a major risk factor for the development of asthma and rhinitis. A workshop on furry animals was convened to provide an up-to-date assessment of our understanding of (1) the exposure and immune response to the major mammalian allergens, (2) the relationship of these responses (particularly those to specific proteins or components) to symptoms, and (3) the relevance of these specific antibody responses to current or future investigation of patients presenting with allergic diseases. In this review by Konradsen et al, research results discussed at the workshop are presented, including the effect of concomitant exposures from other allergens or microorganisms, the significance of the community prevalence of furry animals, molecular-based allergy diagnostics, and a detailed discussion of cat and dog components (J Allergy Clin Immunol 2015; 135: 616-625).

Exposure to allergens from these furry animals is ubiquitous, and the clinician should evaluate all patients with allergic airway disease for sensitization to animal dander. In fact, allergic sensitization to several mammalian animals is prevalent, which might reflect co-sensitization or cross-reactivity. In some countries sensitization to furry animals is associated with more severe allergic disease, which poses extended diagnostic and therapeutic challenges. An important step forward in the diagnosis of allergy to furry animals has been made with the introduction of molecular-based allergy diagnostics, which offer new opportunities for improved characterization. For example, it has been shown that IgE responses to different cat components can be induced through different routes of exposure and are associated with either inhalant symptoms or  food allergy. Cat IgA and other cat proteins carrying alpha-gal are present as minor constituents of cat dander extracts but are better represented in epithelial extracts.  Interestingly, the cross-reactivity between cat and pork albumin is the most consistent.

Although there is clear evidence for the clinical importance of analyzing cat components in relation to both alpha-gal and pork-cat syndrome, the authors believe that future studies will clarify the clinical utility of molecular-based allergy diagnostics in the management of patients sensitized to furry animals. The workshop identified 6 areas for future research related to the specific allergens derived from furry animals that could contribute to our understanding and management of relevant allergic diseases.

Question for the authors:

Based on what is already known about cat allergy, it seems that once an allergy to cat is established, immunotherapy may significantly improve outcomes for patients that suffer from asthma and rhinitis. What is known about cat immunotherapy as it relates to asthma and rhinitis outcomes, regardless of other allergies the patient may have?

Fel d 1 is the most important allergen in cat dander and up to 95% of cat-allergic patients are sensitized to this protein. Subcutaneous immunotherapy (SIT) with cat dander extract has been shown to improve symptom/medication scores for both asthma and rhinoconjunctivitis. In addition, SIT has been shown to decrease skin, conjunctival and bronchial allergen sensitivity and to induce production of IgG and IgG4 antibodies towards Fel d 1. Accordingly, subcutaneous immunotherapy with cat dander extract is considered to be an effective treatment for both allergic asthma and rhinitis. [1-5]

1. Hedlin G, Graff-Lonnevig V, Heilborn H, et al. Immunotherapy with cat- and dog-dander extracts. V. Effects of 3 years of treatment. The Journal of allergy and clinical immunology 1991;87(5):955-64
2. Alvarez-Cuesta E, Cuesta-Herranz J, Puyana-Ruiz J, et al. Monoclonal antibody-standardized cat extract immunotherapy: risk-benefit effects from a double-blind placebo study. The Journal of allergy and clinical immunology 1994;93(3):556-66
3. Van Metre TE, Jr., Marsh DG, Adkinson NF, Jr., et al. Immunotherapy for cat asthma. The Journal of allergy and clinical immunology 1988;82(6):1055-68
4. Varney VA, Edwards J, Tabbah K, et al. Clinical efficacy of specific immunotherapy to cat dander: a double-blind placebo-controlled trial. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 1997;27(8):860-7

5. Hedlin G, Wille S, Browaldh L, et al. Immunotherapy in children with allergic asthma: effect on bronchial hyperreactivity and pharmacotherapy. The Journal of allergy and clinical immunology 1999;103(4):609-14

Wednesday, March 4, 2015

Role of siglecs and related glycan-binding proteins in immune responses and immunoregulation

Recent years have seen a tremendous acceleration of knowledge in the field of glycobiology, revealing many intricacies and functional contributions that were previously poorly appreciated or even unrecognized. This review by Bochner and Zimmermann highlights several topics relevant to glycoimmunology in which mammalian and pathogen-derived glycans displayed on glycoproteins and other scaffolds are recognized by specific glycan-binding proteins (GBPs), leading to a variety of proinflammatory and anti-inflammatory cellular responses (J Allergy Clin Immunol 2015; 135: 598-608). Their main focus is on 2 families of GBPs, sialic acid–binding immunoglobulin-like lectins (siglecs) and selectins, which are involved in multiple steps of the immune response, including distinguishing pathogens from self, cell trafficking to sites of inflammation, fine-tuning of immune responses leading to activation or tolerance, and regulation of cell survival. Importantly for the clinician, accelerated rates of discovery in the field of glycoimmunology are being translated into innovative medical approaches that harness the interaction of glycans and GBPs to the benefit of the host and might soon lead to novel diagnostics and therapeutics.

Lectins are members of families with carbohydrate recognition domains, and glycosaminoglycan-binding proteins, which bind mostly sulfated glycosaminoglycans. The authors focus mainly on sialic acid–binding immunoglobulin-like lectins (siglecs), which are I-type (immunoglobulin superfamily–type) lectins, and selectins, a subset of the C-type (calcium-dependent) lectin family, which collectively function in the immune system in processes such as pathogen recognition and cell adhesion, activation, signaling, and death. The inhibitory function of siglecs is being exploited for suppressing unwanted immune responses, such as autoimmunity, transplantation, allergic diseases, and others. Current therapeutic approaches mainly involve the use of immunosuppressive drugs; however, this compromises normal immunity and thus carries risks. Novel methods are being explored that would induce antigen-specific tolerance while preserving protective immunity.

Although there is great complexity in glycobiology and glycoimmunology, clear patterns for the role of glycans and GBPs in immune responses are emerging. Glycans are one part of the immune system’s ability to distinguish self from danger; however, pathogens can sometimes use their glycocalyx to evade immune recognition. Similarly, cancer cells can adapt their glycome as part of an evolutionary advantage to evade immune reactivity. Glycans and GBPs are part of the regulation of recruitment of immune cells to sites of inflammation, and defects in GPBs or their ligands can lead to immunodeficiencies. The level of immune response or tolerance is regulated in part by glycans and GBPs, and knowledge of this balance is guiding targeted therapy by using novel approaches involving glycans, including vaccination. Several tactics exploiting glycoimmunology have already or will soon make their way to the clinic, and it is anticipated that additional therapeutic approaches will emerge as our understanding of the glycome and its function in immune responses expands.

Question for the authors:
Preserving protective immunity while suppressing unwanted immune responses would have momentous outcomes. Based on current research, when can clinicians expect to see novel therapeutics utilizing glycobiology in clinical trials?

A company called Glycomimetics, Inc. is already in advanced stages of clinical trials with a pan-selectin antagonist (full disclosure:  Dr. Bochner has received shares of stock from them as a result of my consulting efforts with them a few years ago).  Another company, Sialix, is focusing on therapies targeting specific glycans on cancers and other inflammation-related glycans.  We should soon know whether glycan-based vaccines will prove useful, and glycan-based targeting via liposomal delivery of drug payloads shows exciting beneficial effects in pre-clinical testing in various disease models.  So several glycan and glycan-binding protein based therapies are, or will soon be, in clinical trials.