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.

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.  

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.