Severe Asthma in Adults: An Orphan Disease?
Introduction
Although asthma is a prevalent chronic disease, severe asthma that is refractory to treatment is rare. Epidemiologic data on severe asthma prevalence are missing, but severe asthma probably affects approximately 10% of patients with asthma, whereas severe treatment-resistant/refractory asthma probably affects 1% to 2%.1, 2 Moreover, severe asthma is an extremely heterogeneous disease in terms of clinical presentation and pathophysiologic mechanisms. Studies of severe asthma cohorts, such as the European Network for Understanding Mechanisms of Severe Asthma (ENFUMOSA), Severe Asthma Research Program (SARP), the Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens study (TENOR), and single-center cohorts (Table 1),3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 provide important information on severe asthma and introduce the concept of specific phenotypes in terms of clinical, physiologic, pathophysiologic, and treatment response characteristics. Moreover, some patients exhibit concordant disease, such as severe symptoms, inflammation, and impairment, whereas others show discordant disease, with very poor correlation between symptoms, inflammation, bronchial tissue damage, and functional impairment.22 Although important new information has been gained from these recent severe asthma studies, many questions remain unanswered and the issue of treatment is still unresolved.
Management of severe asthma follows the general principles of overall asthma management, and inhaled steroids and long-acting β-agonists remain the cornerstone of treatment. However, severe asthma requires more classes of medication, including oral steroids and omalizumab, and some newer compounds are currently being tested. Nevertheless, a substantial number of patients have severe asthma that remains uncontrolled. Given the poor response to treatment and the side effects associated with medications for severe asthma, such as oral steroids, new pharmaceutical compounds must be developed and their effects examined. However, patients with severe asthma are few, and pathophysiologic mechanisms and responses to treatment must be examined in each phenotypic group within this small population. Therefore, this severe spectrum of the disease likely fits the definition of a rare or orphan disease.
This article briefly describes severe asthma and its definition, risk factors, phenotypes, and treatment options, and provides a definition of orphan disease. Severe asthma remains a challenge to treat, greatly affects the lives of patients, and represents a huge cost to patients and society. New treatment options are needed and their effectiveness should be examined in long-term studies and meticulously characterized cohorts.
Section snippets
Definition of severe asthma
The concept of asthma severity has evolved substantially over the years. In the early Global Initiative for Asthma (GINA) and National Asthma Education and Prevention Program (NAEPP) guidelines, overall asthma severity was assessed primarily based on the patient's clinical characteristics before treatment initiation.23, 24 According to the 2009 World Health Organization Consultation,25 severe asthma comprises three groups: untreated, difficult-to-treat, and treatment-resistant severe.
Untreated
Evaluation and monitoring
In evaluating the patient, the diagnosis of severe asthma must be confirmed and other diseases excluded, such as vocal cord dysfunction, Churg-Strauss syndrome, panbronchiolitis, chronic obstructive pulmonary disease (COPD), and many others that may be associated with asthma.28 Once the diagnosis is confirmed, the physician should assess frequency/severity of symptoms and exacerbations. Validated measures to examine symptom severity, such as dyspnea scales, are valuable indicators of a
Severe asthma phenotypes: a cluster of rare diseases?
Until a few years ago, severe asthma was usually classified in terms such as severe occupational, aspirin-induced, premenstrual, intrinsic, and brittle. These classifications still stand; however, it is more important to classify asthma in terms of clinical presentation, pathophysiologic characteristics, and response to treatment (Box 1). These features include frequency and severity of exacerbations, age of onset, lung function status, risk factors, and comorbidities, and also the extent,
Rare diseases and orphan drugs
No single, satisfactory, worldwide-accepted definition for rare or orphan diseases exists. The United States and Europe have a different set of rules and definitions regarding orphan diseases, whereas country-specific regulations also exist. Most definitions for orphan diseases usually involve the number of people affected by the disease and other factors, such as the lack of available treatments or the severity of the disease.
In the United States, orphan diseases are defined by the Rare
Summary
Is severe asthma, then, an orphan disease? Should severe asthma be disassociated from asthma that responds to treatment? Is it a different disease? And should resources be allocated into research for severe asthma drugs under the orphan drug act? Clearly, a group of patients with severe asthma fits this orphan disease description. They are few, experience symptoms and debilitating restrictions to their daily activities, often experience life-threatening attacks, have asthma that does not
Reference (76)
- et al.
Characterization of the severe asthma phenotype by the National Heart, Lung, and Blood Institute's Severe Asthma Research Program
J Allergy Clin Immunol
(2007) - et al.
Severe asthma: lessons from the Severe Asthma Research Program
J Allergy Clin Immunol
(2007) - et al.
A multivariate analysis of risk factors for the air-trapping asthmatic phenotype as measured by quantitative CT analysis
Chest
(2009) - et al.
Fixed airflow obstruction due to asthma or chronic obstructive pulmonary disease: 5-year follow-up
J Allergy Clin Immunol
(2010) - et al.
Design and baseline characteristics of the epidemiology and natural history of asthma: outcomes and treatment regimens (TENOR) study: a large cohort of patients with severe or difficult-to-treat asthma
Ann Allergy Asthma Immunol
(2004) - et al.
Uniform definition of asthma severity, control, and exacerbations: document presented for the World Health Organization Consultation on Severe Asthma
J Allergy Clin Immunol
(2010) - et al.
Severe asthma in adults: what are the important questions?
J Allergy Clin Immunol
(2007) Asthma: defining of the persistent adult phenotypes
Lancet
(2006)- et al.
Rhinosinusitis in severe asthma
J Allergy Clin Immunol
(2001) - et al.
Causative and contributive factors to asthma severity and patterns of medication use in patients seeking specialized asthma care
Chest
(2003)
Association of obstructive sleep apnea risk with asthma control in adults
Chest
Airway inflammation assessed by invasive and noninvasive means in severe asthma: eosinophilic and noneosinophilic phenotypes
J Allergy Clin Immunol
Exhaled nitric oxide identifies the persistent eosinophilic phenotype in severe refractory asthma
J Allergy Clin Immunol
Uncontrolled asthma: a review of the prevalence, disease burden and options for treatment
Respir Med
Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma
J Allergy Clin Immunol
Does orphan drug legislation really answer the needs of patients?
Lancet
The ENFUMOSA cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma. European Network for Understanding Mechanisms of Severe Asthma
Eur Respir J
The response to combination therapy treatment regimens in severe/difficult-to-treat asthma
Eur Respir J
Differences in airway inflammation in patients with fixed airflow obstruction due to asthma or chronic obstructive pulmonary disease
Am J Respir Crit Care Med
Risk factors and characteristics associated with severe and difficult to treat asthma phenotype: an analysis of the ENFUMOSA group of patients based on the ECRHS questionnaire
Clin Exp Allergy
Analysis of induced sputum in adults with asthma: identification of subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids
Thorax
Consistently very poorly controlled asthma, as defined by the impairment domain of the Expert Panel Report 3 guidelines, increases risk for future severe asthma exacerbations in The Epidemiology and Natural History of Asthma: outcomes and treatment regimens (TENOR) study
J Allergy Clin Immunol
Analyses of asthma severity phenotypes and inflammatory proteins in subjects stratified by sputum granulocytes
J Allergy Clin Immunol
Obesity and asthma: an association modified by age of asthma onset
J Allergy Clin Immunol
TENOR risk score predicts healthcare in adults with severe or difficult-to-treat asthma
Eur Respir J
Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program
Am J Respir Crit Care Med
Clinical characteristics and prognosis in near-fatal asthma patients in Salvador, Brazil
J Bras Pneumol
Near-fatal asthma phenotype in the ENFUMOSA Cohort
Clin Exp Allergy
Factors associated with persistent airflow limitation in severe asthma
Am J Respir Crit Care Med
“Refractory” eosinophilic airway inflammation in severe asthma: effect of parenteral corticosteroids
Am J Respir Crit Care Med
Risk factors of frequent exacerbations in difficult-to-treat asthma
Eur Respir J
Airway inflammation in obese and nonobese patients with difficult-to-treat asthma
Allergy
Cluster analysis and clinical asthma phenotypes
Am J Respir Crit Care Med
Guidelines for the diagnosis and management of asthma
Asthma management and prevention
Difficult/therapy-resistant asthma: the need for an integrated approach to define clinical phenotypes, evaluate risk factors, understand pathophysiology and find novel therapies. ERS Task Force on Difficult/Therapy-Resistant Asthma. European Respiratory Society
Eur Respir J
Proceedings of the ATS workshop on refractory asthma: current understanding, recommendations, and unanswered questions. American Thoracic Society
Am J Respir Crit Care Med
Diagnosis and definition of severe refractory asthma: an international consensus statement from the Innovative Medicine Initiative (IMI)
Thorax
Cited by (17)
Severe Asthma Standard-of-Care Background Medication Reduction With Benralizumab: ANDHI in Practice Substudy
2023, Journal of Allergy and Clinical Immunology: In PracticeEffective Management of Severe Asthma with Biologic Medications in Adult Patients: A Literature Review and International Expert Opinion
2022, Journal of Allergy and Clinical Immunology: In PracticeLong-term effect of home-based pulmonary rehabilitation in severe asthma
2019, Respiratory MedicineCitation Excerpt :It is a retrospective observational study. The study sample is small however severe asthma is akin to “rare diseases” [30]. Patients were not randomised and the choice to join the home-based PR program was based on the patient's personal preference and/or on the absence of a local PR centre.
Innate immunity as the orchestrator of allergic airway inflammation and resolution in asthma
2017, International ImmunopharmacologyCitation Excerpt :Allergic asthma is a heterogeneous disease of the conducting airways characterized by variable airflow obstruction coupled with airway hyperresponsiveness (AHR) that occurs following exposure to allergic stimuli in genetically susceptible individuals. Asthma-related symptoms include wheezing, dyspnea, cough and sputum production [1,2]. Central to the pathophysiology of asthma is the initiation and perpetuation of allergen-driven airway inflammation which is triggered through activation of the innate and adaptive arms of the immune system.
Novel Biomarkers in Severe Asthma
2017, Archivos de Bronconeumologia
Financial disclosures and/or conflicts of interest: The authors have nothing to disclose.