Uniform definition of asthma severity, control, and exacerbations: Document presented for the World Health Organization Consultation on Severe Asthma

Article Outline

• Abstract
• Goal of the WHO consultation
• Management of asthma
  • Diversity of asthma management across the world
  • WHO model list of essential medicines
  • Assuring quality of inhalation products
  • Efficacy and effectiveness of interventions for asthma management
• Proposal for a uniform definition of asthma severity
  • Components of asthma severity
    • Level of control
    • Risk
  • Exacerbations
  • Responsiveness to therapy
  • Assessment of severity
• Uniform definition of severe asthma
• Subphenotyping of severe/uncontrolled asthma
• Asthma and wheezing in children
• Applicability of the proposed definitions of severe asthma
  • Public health
  • Clinical practice
  • Registries on severe asthma
  • Clinical trials
  • Research on asthma mechanisms and genetics
  • Epidemiologic studies
  • Applicability to developed and developing countries
  • Conclusion
• Acknowledgment
• References
• Copyright

Asthma is a global health problem affecting around 300 million individuals of all ages, ethnic groups and countries. It is estimated that around 250,000 people die prematurely each year as a result of asthma. Concepts of asthma severity and control are important in evaluating patients and their response to treatment, as well as for public health, registries, and research (clinical trials, epidemiologic, genetic, and mechanistic studies), but the terminology applied is not standardized, and terms are often used interchangeably. A common international approach is favored to define severe asthma, uncontrolled asthma, and when the 2 coincide, although adaptation may be required in accordance with local conditions. A World Health Organization meeting was convened April 5-6, 2009, to propose a uniform definition of severe asthma. An article was written by a group of experts and reviewed by the Global Alliance against Chronic Respiratory Diseases review group. Severe asthma is defined by the level of current clinical control and risks as “Uncontrolled asthma which can result in risk of frequent severe exacerbations (or death) and/or adverse reactions to medications and/or chronic morbidity (including impaired lung function or reduced lung growth in children).” Severe asthma includes 3 groups, each carrying different public health messages and challenges: (1) untreated severe asthma, (2) difficult-to-treat severe asthma, and (3) treatment-resistant severe asthma. The last group includes asthma for which control is not achieved despite the highest level of recommended treatment and asthma for which control can be maintained only with the highest level of recommended treatment.

Key words: Asthma, severity, control, risk, definition, GARD

Abbreviations used: ATS, American Thoracic Society, COPD, Chronic obstructive pulmonary disease, DPI, Dry powder inhaler, EPR3, Expert Panel Report 3, ERS, European Respiratory Society, GINA, Global Initiative for Asthma, ICS, Inhaled corticosteroid, LABA, Long-acting ß₂-agonist, LMIC, Low-income and middle-income country, MDI, Metered-dose inhaler, NAEPP, National Asthma Education Prevention Program, OCS, Oral corticosteroid, PEF, Peak expiratory flow, PHC, Primary heath care, WHO-PEN, World Health Organization Package of Essential Interventions for Noncommunicable Diseases, WHO, World Health Organization

Discuss this article on the JACI Journal Club blog: www.jaci-online.blogspot.com.

Asthma is a global health problem affecting around 300 million individuals of all ages, ethnic groups, and countries.¹ It is estimated that around 250,000 people die prematurely each year as a result of asthma.¹ However, due to geographical diversity, there is a considerable heterogeneity of asthma in terms of gene-environment interactions, pathophysiological mechanisms, environmental exposures, comorbidities, age, underlying disease severity, health care access, care received, psychological factors, responsiveness of disease to therapy, and burden of disease including asthma exacerbations and death as well as long-term chronic morbidity.²

Concepts of asthma severity and control are important in evaluating patients and their response to treatment as well as for public health, registries, and research (clinical trials, epidemiologic, genetic, and mechanistic studies), but the terminology applied is not standardized, and terms are often used interchangeably. A common international approach is favored to define severe asthma, uncontrolled asthma, and when the 2 coincide,³ although adaptation may be required in accordance with local conditions.

In 2008, an American Thoracic Society (ATS)/European Respiratory Society (ERS) Task Force reported some new perspectives on asthma control and severity to achieve uniform reporting of clinical trials.⁴ These concepts were appropriate for patients who have access to optimal drug treatments and to evaluate the response of patients to these interventions. Asthma in preschool children was not included, nor were aspects of severity related to public health issues and management in high-income countries or low-income and middle-income countries (LMICs).⁵, ⁶

The first asthma guidelines were constructed on the idea that the practitioner first assessed and then graded asthma severity.⁷ The major reasons to characterize asthma severity were to guide management and to identify people with asthma at risk of severe exacerbation. Unfortunately, the case definitions of asthma severity and control were not always clear, and over the last 2 decades, they varied between and within asthma management guidelines. Initially, asthma guidelines proposed a stepwise management according to disease severity⁷ that was based on symptoms, the need for rescue medications, and lung function tests (eg, peak expiratory flow [PEF] rate and FEV₁). However, as it became increasingly recognized that categorizing asthma involved assessing both the severity of the underlying disease and its responsiveness to treatment,⁸, ⁹, ¹⁰ later iterations of the guidelines viewed asthma severity according to the current treatment the patient was receiving.¹¹, ¹²

The classification of asthma by severity has raised concerns.¹³, ¹⁴, ¹⁵, ¹⁶ Severity is not a stable feature of asthma but may change with time, whereas the classification by disease severity suggests a static feature. Moreover, the term severity is used variably to indicate current symptoms, the resistance of symptoms to standard treatment, and future risk of death or exacerbations. Responsiveness to treatment is heterogeneous, even among patients with asthma of similar severity. Moreover, the use of severity as a single outcome measure has limited value in predicting which treatment will be required and the response to that treatment.¹⁷, ¹⁸ These considerations prompted some guideline committees to propose that asthma severity is no longer used as the basis for treatment decisions, and that the focus is more so to assess current clinical asthma control first¹⁹ and then to adjust treatment accordingly in a stepwise manner.¹¹ The National Asthma Education Prevention Program (NAEPP)–Expert Panel Report 3 (EPR3) proposed that the concepts are linked: severity is the intrinsic intensity of the disease, control is the degree to which the manifestations of asthma are minimized by treatment, and responsiveness is the ease with which asthma control is achieved. EPR3 further proposed that severity and control incorporate 2 distinct domains: impairment (frequency and intensity of symptoms and functional limitations currently experienced) and risk (likelihood of exacerbations, progressive decline in lung function or, for children, reduced lung growth, or risk of medication side effects).²⁰, ²¹

A guideline for the management of asthma in LMICs has been published by The Union (International Union Against Tuberculosis and Lung Disease) based on the Global Initiative for Asthma (GINA) 1995 and adapted to the availability and affordability of medications²² and the World Health Organization (WHO) Model List of Essential Medicines. An update was published in 2008.²³ In these guidelines, inhaled corticosteroids (ICSs) as potent anti-inflammatory drugs are proposed as the mainstay treatment for the management of asthma based on disease severity as assessed by symptoms and lung function measurement.

All asthma guidelines propose that for an individual patient, the practitioner should perform a periodic assessment of asthma control and adjust treatment accordingly.¹¹, ¹², ²⁰, ²³, ²⁴, ²⁵ This is particularly important in children, in whom remission of asthma is common.

Three important issues regarding the current global situation for asthma management have led to the proposal for the uniform definition of severe asthma. First, health care provision in different countries is disparate, especially in LMICs, which have limited or no access to chronic medical care or asthma therapies. Second, with appropriate management,¹¹, ¹², ²⁰, ²³, ²⁴, ²⁵ the control of asthma can be achieved adequately in most patients. Third, direct and indirect costs for asthma are substantial, in particular in low-resource settings.²⁶, ²⁷ Thus, a standardized definition of severe asthma will promote efficient identification and treatment of patients. These patients will benefit from treatment, and, in turn, this will ease the burden of the disease on patients, their families, and society.

The proposal for a uniform definition of asthma severity, control, and exacerbations has taken into account the GINA 2006 revision,¹¹ the 2007 NAEPP-EPR3,²⁰ The Union 2008 guide,²³ and the 2008 ATS/ERS Task Force report⁴ and has considered the previous definitions of the 2 ERS²⁸ and ATS Task Forces,⁸ in which the terms “severe,” “therapy-resistant asthma,” “refractory asthma,” or “difficult-to-control asthma” were applied to patients with symptomatic asthma on current treatment.

Back to Article Outline

Goal of the WHO consultation 

The goal of the WHO Consultation on Severe Asthma (Geneva, April 6-7, 2009) was to propose a WHO definition of asthma severity and control as well as criteria for describing exacerbations and their severity, which should be applicable in most circumstances in low-, middle-, and high-income countries.

Back to Article Outline

Management of asthma 

Diversity of asthma management across the world 

The management of asthma differs widely and is dependent on patients' centered problems (socioeconomic and cultural barriers) as well as national, economic, and health provider settings. In high-income countries, most antiasthma treatments are available and, for the majority of patients, are affordable. Therefore, asthma management in these countries is possible using guidelines formulated without respect to medication availability, cost, and affordability. However, in many LMICs, essential medicines may be available but are rarely affordable.²⁹, ³⁰ In these settings, patients and health care providers are used to short-term continuous treatments for most communicable diseases and do not easily understand the need for long-term treatments. In the primary health care (PHC) settings of LMICs, only syndromic approaches for major noncommunicable diseases are applicable.³¹, ³² In many LMICs, the availability of objective pulmonary function testing such as spirometry and PEF measurement is also problematic, although the availability and use of PEF has recently been recommended to all PHC facilities (WHO Package of Essential Interventions for Noncommunicable Diseases [WHO-PEN]).³³ Hence, both adequate treatments and organized health care systems are needed, as well as an appropriate communication to health care providers and patients.

WHO model list of essential medicines 

The current Model List of Essential Medicines was prepared by a WHO Expert Committee in March 2007 and represents its 15th edition³⁴ (Table I).

Table I. WHO model list of essential medicines for asthma and COPD³⁴

The square box symbol (□) is primarily intended to indicate similar clinical performance within a pharmacologic class. The listed medicine should be the example of the class for which there is the best evidence for effectiveness and safety. In some cases, this may be the first medicine that is licensed for marketing; in other instances, subsequently licensed compounds may be safer or more effective. Where there is no difference in terms of efficacy and safety data, the listed medicine should be the one that is generally available at the lowest price, based on international drug price information sources.

In principle, essential medicines are those that satisfy the priority health care needs of the population, and they are selected in regard to disease prevalence, evidence on efficacy and safety, and comparative cost-effectiveness. Although a central repository of treatments for severe asthma worldwide is clearly desirable, selection, updating, and assessment of the efficacy of current and novel medicines are difficult tasks, and cost-effectiveness assessments for different areas of the world are most likely impossible. Furthermore, the requirements and methodology for the assessment and grading of evidence are more demanding and require up-to-date methodology, which necessitates significant resources.

Assuring quality of inhalation products 

To minimize adverse reactions, maximize efficacy, and increase the speed and duration of effect at the site of action, inhalation from a pressurized metered-dose inhaler (MDI), a dry powder inhaler (DPI), or a spacer is the recommended route of administration for the majority of medicines for asthma or chronic obstructive pulmonary disease (COPD; corticosteroids, ß₂-agonists, and anticholinergics). However, these recommendations imply that only high-quality drugs meeting strict criteria set by drug regulatory authorities are made available. Inhalation dosage forms, such as MDIs and DPIs, are complex, consisting of the active drug substance in an appropriate formulation and a mechanical device component that delivers the formulation to the patient. The formulation of MDIs is contained in canisters under pressure and contains propellants, such as chlorofluorocarbons or hydrofluoroalkans, for aerosolization. In accordance with the Montreal Protocol, the use of chlorofluorocarbons in inhalers is being phased out and replaced by hydrofluoroalkans or by devices that do not use propellants.³⁵, ³⁶ Several hydrofluoroalkan-MDIs are efficient, but hydrofluoroalkans have characteristics that make them different and more difficult to use as propellants than chlorofluorocarbons. The technology to manufacture hydrofluoroalkan-propelled inhalation aerosols is evolving. Many of the inhalation aerosols are suspensions, making it difficult to manufacture them and maintain their quality through the life of the product. The formulation of DPIs generally contains lactose as a bulking agent. Issues related to the use of lactose include varying stability of the product in various temperatures and relative humidity conditions experienced in the world.

Manufacturing of inhalation products is complicated because of the nature of the dosage form. There are various guidance documents issued by regulatory agencies that advise the industry on producing quality inhalation products.³⁷, ³⁸, ³⁹, ⁴⁰ The critical elements of inhalation dosage forms are assurance of consistent particle size, distribution of the active moiety, dose content uniformity throughout the life of the product, spray pattern and plume geometry, controls for impurities, degradation products, extractability, and leachability. For DPIs, additional critical elements include control for water and moisture content. Ruggedness and reliability of the product under conditions of patients' use are important for all inhalation dosage forms.

The catastrophic failure of an MDI or DPI resulting in little, no, or excess delivery of the active drug substance will place patients with asthma at substantial risk. Failure of an MDI or DPI containing a controller drug such as ICS may go unnoticed by patients because their asthma may not worsen acutely. Furthermore, propellants and excipients in MDIs or lactose in DPIs, which make up the bulk of the drug product formulation, may give the sensation that patients are receiving the drug, whereas in reality they may be getting no active drug substance. Such failures of MDIs and DPIs have been reported in developed countries and have resulted in market withdrawal of products,⁴¹ regulatory action,⁴² and public concern.⁴³

The Union Asthma Drug Facility provides quality-assured hydrofluoroalkan inhalers subjected to specific testing and then certified by using a quality assurance system based on WHO norms and standards.⁵

Health care providers should also be cognizant that inhalation dosage forms are complex and should keep in mind the possibility of device failure or improper use when encountering patients who seem to have worsening asthma despite compliance with medications.

Efficacy and effectiveness of interventions for asthma management 

Studies at the community level on the effectiveness of good asthma care in whole populations reveal a considerable reduction of both hospitalizations and deaths⁴⁴, ⁴⁵, ⁴⁶, ⁴⁷, ⁴⁸ as a result of initiating recommended treatment. All of these intervention programs are also cost-effective.⁴⁵ Such public health strategies for asthma include affordability and accessibility to controller treatments, education of patients and parents, and cooperation between PHC centers. Some studies have been carried out in LMICs or deprived populations (eg, the US Inner City Asthma in Children,⁴⁹ Belo Horizonte and Porto Alegre [studies in children, Brazil],⁵⁰ and Salvador [study in adults, Brazil ]⁵¹). A pilot study conducted in several LMIC sites found that after 1 year of the effective asthma treatment of applying The Union asthma management approach,²² and of using essential medicines,⁵ asthma control improved dramatically.⁵²

Back to Article Outline

Proposal for a uniform definition of asthma severity 

Components of asthma severity 

The concepts of asthma severity, control, and responsiveness are linked.²⁰, ²¹ Asthma severity is the intrinsic severity of the disease process, asthma control is the degree to which therapy goals are met, and responsiveness is the ease with which asthma control is achieved by therapy. The definition of asthma severity includes all these components, as depicted in Table II.

Table II. Components of asthma severity²⁰

1. Level of control

Current clinical control (impairment): symptoms and functional limitations over previous 2-4 wk

Exacerbations over previous 6-12 mo, including number, severity, and use of systemic corticosteroid

2. Level of current treatment prescribed, inhalation technique, and compliance with treatment

3. Responsiveness to treatment

4. Risk

The level of asthma control incorporates current clinical control and exacerbations (Table III). Current clinical control, or extent of impairment, is the frequency and intensity of symptoms and functional limitations that a patient experiences or has recently experienced as a consequence of asthma and includes measures of day and night symptoms, use of reliever therapy, activity limitations, and lung function. The period for which current clinical control should be assessed is proposed to be the previous 2 to 4 weeks for adults and at least 4 weeks for children. The number of asthma exacerbations requiring oral systemic corticosteroids (for more than 3 days) in the previous year should also be considered in evaluating overall asthma control.

Table III. Level of asthma control in patients ≥5 years of age

Control level	Well controlled†	Partially controlled†	Poorly controlled†
Daytime symptoms in the past 2-4 wk	≤2 d/wk but not more than once a day	>2 d/wk or more than once a day but ≤2 d/wk	Throughout the day
Limitations of activities in the past 2-4 wk	None	Some limitation	Extremely limited
Nocturnal symptoms/awakenings in the past 2-4 wk	None	≤2 nights/wk	>2 nights/wk
Need for short-acting inhaled ß2-agonists in the past 2-4 wk	≤2 d/wk	>2 d/wk	Several times a day
Lung function FEV1 or PEFR∗ FEV1/FVC (<11 y of age)	≥80% predicted or personal best ≥80%	60% to 79% predicted or personal best 75% to 80%	<60% predicted or personal best <75%
Exacerbations (requiring oral or systemic corticosteroids)‡	0-1/y	2/y	Frequent (>2/y)
	Consider severity and interval since last exacerbation

FVC, Forced vital capacity; PEFR, peak expiratory flow rate.

Any of the components places the patient in the category.

Until recently, strong emphasis has been placed on lung function measures such as PEF and FEV₁ before and after bronchodilator as a measure of asthma control or asthma severity. There is an inconsistent relationship between lung function measures and symptoms or exacerbation frequency as patient-centered outcome measures.¹⁰ Therefore, it is important for a comprehensive assessment to capture multiple asthma endpoints, including lung function.

Questionnaires for assessing asthma control have been developed. These tools score asthma indices as continuous variables and thus provide numeric values to distinguish different levels of control (eg, Asthma Control Test,⁵³ Childhood Asthma Control Test, Asthma Control Questionnaire,⁵⁴ Asthma Therapy Assessment Questionnaire,⁵⁵ Royal College of Physicians Questionnaire,⁵⁶ Asthma Control Scoring System⁵⁷). Most of these instruments do not include a measure of lung function.

For PHC centers, WHO has developed a minimal set of criteria to assess noncommunicable diseases including asthma (WHO-PEN) that can be used for determining the level of asthma control. The components of asthma control used in this declaration are daytime symptoms, nighttime symptoms, needs for rescue medications, limitations of daily physical activity, exacerbations requiring oral or injectable corticosteroid, and PEF.

The concept of asthma risk²⁰ is intended to capture the following:

Exacerbations 

Exacerbations (commonly referred to as asthma attacks or acute asthma) are episodes of progressive increase in shortness of breath, cough, wheezing, chest tightness, or a combination of these symptoms. Exacerbations are characterized by decreases in expiratory airflow (PEF or FEV₁). However, PEF variability does not usually increase during an exacerbation, although it may do so leading up to or during the recovery from an exacerbation.⁶⁰ The severity of exacerbations ranges from mild to life-threatening and can be evaluated based on both symptoms and lung function. Exacerbations should be considered separately from current clinical control (impairment) when evaluating overall asthma control because exacerbations may occur even if the patient has adequate day-to-day control of symptoms and minimal activity limitations. Such exacerbations may or may not be prevented by escalating maintenance therapy.

In GINA 2006¹¹ and NAEPP-EPR3 2007,²⁰ moderate or severe asthma exacerbations are those that require treatment with systemic corticosteroids. More frequent and intense exacerbations, requiring urgent, unscheduled care, an emergency department visit, hospitalization, or intensive care unit admission, indicate poorer overall disease control.

Responsiveness to therapy 

Responsiveness to therapy is the ease with which asthma control is achieved by therapeutic interventions. The degree of responsiveness to therapy will determine the amount of medication required to achieve asthma control (as defined in Table III) and is considered a key element of assessing severity during treatment (Table II).

Several levels of responsiveness to treatment are recognized:

Assessment of severity 

The ATS/ERS Task Force on the definition of asthma severity and control proposed not to retain a definition of severity in patients in the absence of treatment because pretreatment features do not usually predict subsequent response to therapy.⁴ However, many (if not most) people with asthma in the world, particularly in LMICs, do not have access to effective medications (medications may be unavailable or unaffordable or the individual may not have received a diagnosis or been prescribed appropriate treatment). To help with disease management and to allow for appropriate epidemiologic assessments, it is important that disease severity be determined in the absence of treatment if patients are currently untreated.

Asthma severity may be influenced by genetic and environmental factors, the underlying disease activity, and the patient's disease pathobiological processes. These differ between patients with differing phenotypes, which may be further described using a combination of pathological and physiological markers.⁴ These markers might also serve as surrogate disease measures for gauging future risk and are discussed further in the section “Subphenotyping of severe/uncontrolled asthma.” It is possible that the phenotypes of severe untreated and severe asthma differ during treatment.

Asthma severity is thus measured either before treatment is initiated, for the untreated patients, or during treatment.

Before treatment, the historical severity should be assessed by reviewing the patient's history of asthma control over a sufficient period (ideally 6-12 months) to better assess the intrinsic severity of the disease and to avoid seasonal variations. It may be evaluated using the criteria used for the assessment of asthma control (Table III). Using these criteria, a patient would be considered to have untreated severe asthma if the history indicated partially or poorly controlled asthma over a sufficient period.

During treatment, the level of severity is determined by correlating it with the minimal level of medications required to maintain asthma control (see section “Responsiveness to therapy”). Assessment of adherence to prescribed treatment is essential, for example, by sensitive inquiry, prescription monitoring, or tablet counting. Risks should also be assessed (Table II). Although data are lacking to correlate specific levels of risk to severity, in general, the greater the frequency and intensity of the side effects of medication or occurrence of exacerbations, or the documentation of progressive lung function or reduced lung growth, the higher the level of asthma severity. Generally, the duration over which disease severity should be assessed is between 6 and 12 months.

Back to Article Outline

Uniform definition of severe asthma 

Severe asthma is defined by the level of current clinical control and risks as “Uncontrolled asthma which can result in risk of frequent severe exacerbations (or death) and/or adverse reactions to medications and/or chronic morbidity (including impaired lung function or reduced lung growth in children).”

Severe asthma includes 3 groups, each carrying different public health messages and challenges:

This document also includes wheezing disorders in preschool children. Although there is dispute as to the age at which the label asthma can properly be applied,⁵⁹ for the purpose of the document, infants and preschool children with wheeze not related to a specific underlying diagnosis such as cystic fibrosis are included.

The definitions help support the treatment of patients with asthma including both the level of current clinical control and the risk of deterioration. They may be particularly useful for the following:

A decision tree (Fig 1) represents how to characterize the 3 groups of severe asthma (untreated severe asthma, treatment-resistant severe asthma, and difficult-to-treat severe asthma). The characterization of severe asthma is based on successive assessments of asthma control, which can be evaluated by using different methods according to the setting and management strategies, including applying the criteria in Table III or using WHO-PEN. Patients with poorly controlled asthma are at risk of developing severe exacerbations and chronic morbidity. Many patients consulting for severe asthma do not have asthma, and some patients with mild/moderate asthma present with another condition (eg, bronchiectasis, dysfunctional breathing, vocal cord dysfunction, and so forth) that is causing severe symptoms in addition to their background asthma.⁶⁸

• 
  • View Large Image
  • Download to PowerPoint

• Fig 1. 

  Decision-making steps for characterizing severe asthma, with correlating action steps for clinical management. PF, Pulmonary function.

Back to Article Outline

Subphenotyping of severe/uncontrolled asthma 

Asthma is a complex, multidimensional disease with marked heterogeneity. Tools to phenotype individual asthma subtypes are now being developed to characterize the various patterns of triggers that induce symptoms, different clinical presentations of the disease, and different inflammatory markers (Fig 2). Phenotyping subtypes can be used to characterize and predict disease severity, progression, and response to treatment and may help identify targets for treatment. Heterogeneity also exists within each dimension of the disease (eg, eosinophils and asthma severity),⁶⁹, ⁷⁰ across diseases (eg, eosinophils in asthma and COPD), and in relation to comorbidities.², ⁷¹ Phenotypes may also change over time both within and across countries.

• 
  • View Large Image
  • Download to PowerPoint

• Fig 2. 

  Increasing detail and precision for phenotypic characterization to provide a more comprehensive and integrated understanding of asthma by taking into account multidimensional features. Although costs escalate with increasing granularity, comprehensive phenotyping may reveal subclinical phenotypes with distinct pathophysiologic pathways for individualizing patient treatment. PGx, A designation for pharmacogenomics; Rx, pharmacologic.

Phenotype heterogeneity may be hypothesis-driven or hypothesis-generating (multiple logistic regression², ⁷²; cluster analysis⁷¹, ⁷³). However, it is necessary to commence with a WHO definition that can be applied worldwide. The subphenotyping of severe asthma may then be attempted with the following approaches:

Back to Article Outline

Asthma and wheezing in children 

Childhood asthma represents a serious problem worldwide with increasing trends in LMICs.⁸⁴ In childhood asthma, specific factors need to be considered including environmental factors (eg, sensitization to allergens, early-age smoking and environmental tobacco smoke, early-life infections, food allergy), correct use of medications (eg, spacers) and fear of ICS. Moreover, asthma severity in children may be very different from that in adults (eg, baseline airway caliber often normal, highly responsive to viral infections, exercise, foods).

The roots of much adult airway disease lie antenatally and in the very early preschool years, hence the importance of this age group. Antenatal factors, in particular maternal smoking and maternal atopic status,⁸⁵, ⁸⁶ but also other factors such as environmental pollutant exposure,⁸⁷, ⁸⁸ maternal diabetes, use of antibiotics,⁸⁹ and possibly transgenerational effects of grandparental smoking, affect infant lung health and immune responses in cord blood. Taken together, these affect the severity of viral infections in the preschool years, in particular rhinovirus, and these are associated with wheeze persisting into mid-childhood.⁹⁰, ⁹¹ Infants who will later develop persistent wheeze are born with essentially normal lung function, but will have developed airway obstruction by age 4 to 6 years.⁹², ⁹³ Airway wall histology is normal at age 1 year, and bronchoalveolar lavage predominantly shows a neutrophilic phenotype.⁹⁴ By age 2.5 years and even earlier,⁹⁵, ⁹⁶ structural airway wall changes and eosinophilic inflammation have started to appear.⁹⁷ The epidemiologic evidence also underscores the importance of the early years.⁹⁸ It has been shown by a succession of overlapping studies that lung function tracks from age 6 years into late middle age.⁹³, ⁹⁹

There is poor agreement on the definitions of different phenotypes of preschool wheezing disorders. An ERS Task Force⁵⁹ proposed the use of the following terms: episodic (viral) wheeze to describe children who wheeze intermittently with upper respiratory viral infections and who feel well between episodes, and multiple-trigger wheeze for children who wheeze both during and outside discrete viral episodes. Although there was no consensus, the ERS Task Force proposed that the term asthma should probably not be used in preschool children because data regarding underlying inflammation are lacking.⁵⁹ Tools to predict progression to persistent asthma in childhood are not yet available for widespread clinical use,¹⁰⁰, ¹⁰¹, ¹⁰² and there are no disease-modifying strategies to prevent this progression from happening.¹⁰³, ¹⁰⁴, ¹⁰⁵, ¹⁰⁶ In the preschool child, alternative diagnoses are more common, and medication delivery may be much more difficult. Some medications may not have the same efficacy in preschool and older children (eg, LABAs).

The definition of severe asthma as reported is applicable in this age group, but difficult-to-treat severe asthma and treatment-resistant severe asthma are proposed to be listed as “problematic severe asthma” until a detailed evaluation has separated the 2.¹⁰⁷

Although most children with asthma are easy to treat with medications that are both safe and effective, some remain symptomatic despite using high doses of medications.¹⁰⁸ The nomenclature for this group is confusing, and studies are difficult to compare because of the variety of terms that are currently used.³ The approach to “problematic severe asthma” varies with the age of the child. In school children and adolescents, guidelines usually propose an approach similar to that in adults for the definition of control and severity²⁰ (Table II, Table III).

The phenotypes of “problematic severe asthma” show age-related differences. Initially, episodic (viral) exacerbations are common; subsequently, a multitrigger phenotype becomes prominent.

In children ≥5 years, as in adults, severe asthma includes untreated severe asthma, difficult-to-control asthma, and treatment-resistant severe asthma. However, it should be noted that comorbidities may differ in children and adults and that asthma-inducing precipitous and severe exacerbations (sometimes referred to as brittle asthma) may be more common. Phenotypes of severe asthma in children vary from those of adults and change more rapidly. It is therefore necessary to reassess phenotypes at regular intervals.

In preschool children, recurrent, episodic (viral) wheeze appears to be the most common pattern. Morbidity including hospitalization is common for respiratory viral infections. However, allergic asthma may develop very early in life. Pathophysiology in this age group is different from that in adults,⁵⁹ responses to different drugs differ,¹⁰⁹ and adverse effects of corticosteroids on growth and bone maturation in children mean that different treatment strategies are needed.¹¹⁰ A family history of asthma and the presence of allergy are important for symptom persistence into mid-childhood.

In LMICs, asthma in children is highly prevalent, may be more severe than in high-income countries, and is often undiagnosed, in particular because of the lack of training of health care professionals.

Back to Article Outline

Applicability of the proposed definitions of severe asthma 

Public health 

For public health purposes, a uniform definition of severe asthma is needed to identify those patients who require particular attention, to ensure appropriate treatment and regular monitoring, and to improve adherence to treatment to reduce the use of emergency departments and hospitalizations. The aim is to optimize health care planning and policies. This definition will also contribute to accurate estimates of the prevalence of severe asthma and provide support for more precise calculations on the needs for medications in a country. On the basis of the prevalence of severe asthma, the risk of health resource use and deaths is associated with lack of proper management.

Clinical practice 

These WHO definitions provide a framework upon which decisions can be made as to who needs targeting for treatment or improved treatment, especially in LMICs.

Registries on severe asthma 

Severe asthma registries provide a foundation to generate a greater understanding of public health need, and to define phenotypic heterogeneity. They are used for the surveillance of severe asthma.

Several national registries for severe asthma in adults and children already exist, and some are planned. Although there is considerable commonality between these registries, there are also differences. The establishment of an internationally agreed severe asthma definition will facilitate the alignment of current registries. Such a definition will also provide the opportunity to develop a single registry to capture core information in both developed and developing countries.

Clinical trials 

For clinical trials, clarity is essential as to which definitions have been used—severity assessed before treatment or after treatment—and also, which treatment was used.

Research on asthma mechanisms and genetics 

There is an urgent need for more research into severe asthma. We need to improve our understanding of the underlying causes of the disease in order to develop new strategies with an aim to control and therefore eradicate severe asthma. A global definition and a collaborative approach to epidemiologic, genetic, and mechanistic research are important. As highlighted, the challenges for the groups of severe asthma are different. Difficult-to-treat severe asthma requires further research into the role of the comorbidities, cofactors, and psychosocial issues discussed. Strategies need to be developed to improve psychosocial issues and determine their relative importance in contributing to the severity of disease. For treatment-resistant severe asthma, more detailed cellular and molecular phenotyping is needed to identify new targets for the potential development of novel therapies and to target current therapies. Different levels of phenotype characterization (granularity) can be applied to assess phenotypic characterization in patients with severe asthma (Fig 2). For the success of such approaches, it is important to develop global partnerships and platforms to ensure the application of standard methodology, protocols to promote sharing of samples, data to create methods, and infrastructures to collect data and samples from different countries.

Epidemiologic studies 

In epidemiologic population studies, it is often difficult to assess severity because many patients are undertreated based on guideline recommendations. The WHO definition of severe asthma accounts for these patients and articulates time frames for the appropriate assessment of severity and control. Thus, the definition will facilitate epidemiologic research and comparisons across studies in different populations.

Control usually refers to events occurring recently (over the last 2-4 weeks), whereas severity refers to those occurring over a long period (eg, 6-12 months).

Applicability to developed and developing countries 

A WHO definition of severe asthma is needed and should be applicable to the local and geographic conditions of all countries, phenotypes, risk factors, and availability and affordability of treatment, differing widely around the world. Research must be planned to evaluate the phenotypes of severe asthma in different countries.

Conclusion 

Severe asthma broken down into untreated severe asthma, difficult-to-treat asthma, and therapy-resistant asthma remains a major global health problem, particularly in areas or jurisdictions where recommended treatments are not available or affordable, as well as in patients not receiving adequate treatment. Severe asthma is associated with uncontrolled asthma and the increased risk of developing severe and life-threatening exacerbations as well as chronic morbidity such as decline in lung function or reduced lung growth (in children). ICSs represent the mainstay treatment for the prevention and control of severe asthma, and it has been shown that in places where national or local intervention programs exist, there is a considerable cost-effective reduction in asthma hospitalizations and deaths as well as an improved quality of life overall. Children need particular attention because the onset of asthma occurs most frequently in childhood, and management has lifelong consequences on productivity and quality of life. Severe asthma should be managed by appropriate measures as depicted in Table VI. Through the mobilization of health care systems and professionals and access to appropriate medications, it should be possible to reduce the burdens associated with severe/uncontrolled asthma. For people with severe asthma in whom severity cannot be improved with existing therapies, new forms of treatment including preventive strategies are necessary and could be discovered through the global collaboration of databases and biobanks of these patients.

Table VI. Proposals for the management of severe asthma

Although some patients still present with severe asthma despite adequate current management, the following declaration should guide future asthma programs worldwide:

Back to Article Outline

We thank Ms Anna Bedbrook for her administrative help in the preparation of this article.

Back to Article Outline

References 

1. Bousquet J, Khaltaev N. Global surveillance, prevention and control of chronic respiratory diseases: a comprehensive approach. Global Alliance against Chronic Respiratory Diseases. Geneva: World Health Organization; 2007;
   • View In Article
2. Wenzel SE. Asthma: defining of the persistent adult phenotypes. Lancet. 2006;368:804–813
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (279 KB)
   • CrossRef
3. Bush A, Hedlin G, Carlsen KH, de Benedictis F, Lodrup-Carlsen K, Wilson N. Severe childhood asthma: a common international approach?. Lancet. 2008;372:1019–1021
   • View In Article
   • Full Text
   • Full-Text PDF (82 KB)
   • CrossRef
4. Taylor DR, Bateman ED, Boulet LP, Boushey HA, Busse WW, Casale TB, et al. A new perspective on concepts of asthma severity and control. Eur Respir J. 2008;32:545–554
   • View In Article
   • CrossRef
5. Ait-Khaled N, Enarson DA, Bissell K, Billo NE. Access to inhaled corticosteroids is key to improving quality of care for asthma in developing countries. Allergy. 2007;62:230–236
   • View In Article
   • MEDLINE
   • CrossRef
6. Mallol J, Castro-Rodriguez JA, Cortez E, Aguirre V, Aguilar P, Barrueto L. Heightened bronchial hyperresponsiveness in the absence of heightened atopy in children with current wheezing and low income status. Thorax. 2008;63:167–171
   • View In Article
   • CrossRef
7. Bousquet J, Clark TJ, Hurd S, Khaltaev N, Lenfant C, O'byrne P, et al. GINA guidelines on asthma and beyond. Allergy. 2007;62:102–112
   • View In Article
   • MEDLINE
8. Proceedings of the ATS workshop on refractory asthma: current understanding, recommendations, and unanswered questions. American Thoracic Society. Am J Respir Crit Care Med. 2000;162:2341–2351
   • View In Article
9. 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. 2003;22:470–477
   • View In Article
   • MEDLINE
   • CrossRef
10. Moore WC, Bleecker ER, Curran-Everett D, Erzurum SC, Ameredes BT, Bacharier L, 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;119:405–413
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (162 KB)
    • CrossRef
11. Bateman ED, Hurd SS, Barnes PJ, Bousquet J, Drazen JM, FitzGerald M, et al. Global strategy for asthma management and prevention: GINA executive summary. Eur Respir J. 2008;31:143–178
    • View In Article
    • CrossRef
12. British Thoracic Society Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma. Thorax. 2008;63(suppl 4):iv1–121
    • View In Article
    • CrossRef
13. Cockcroft DW, Swystun VA. Asthma control versus asthma severity. J Allergy Clin Immunol. 1996;98(6 Pt 1):1016–1018
    • View In Article
    • Full Text
    • Full-Text PDF (299 KB)
    • CrossRef
14. Sawyer G, Miles J, Lewis S, Fitzharris P, Pearce N, Beasley R. Classification of asthma severity: should the international guidelines be changed?. Clin Exp Allergy. 1998;28:1565–1570
    • View In Article
    • MEDLINE
    • CrossRef
15. Chanez P, Wenzel SE, Anderson GP, Anto JM, Bel EH, Boulet LP, et al. Severe asthma in adults: what are the important questions?. J Allergy Clin Immunol. 2007;119:1337–1348
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (201 KB)
    • CrossRef
16. Wenzel SE, Busse WW. Severe asthma: lessons from the Severe Asthma Research Program. J Allergy Clin Immunol. 2007;119:14–21quiz 22-23
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (249 KB)
    • CrossRef
17. Stoloff SW, Boushey HA. Severity, control, and responsiveness in asthma. J Allergy Clin Immunol. 2006;117:544–548
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (101 KB)
    • CrossRef
18. Bateman ED. Severity and control of severe asthma. J Allergy Clin Immunol. 2006;117:519–521
    • View In Article
    • Full Text
    • Full-Text PDF (68 KB)
    • CrossRef
19. Boulet LP, Phillips R, O'Byrne P, Becker A. Evaluation of asthma control by physicians and patients: comparison with current guidelines. Can Respir J. 2002;9:417–423
    • View In Article
    • MEDLINE
20. NAEPP (National Asthma Education and Prevention Program) Expert panel report 3: guidelines for the diagnosis and management of asthma. 2007. Available at: http://www.nhlbi.nih.gov/guidelines/asthma/index.htm. Accessed September 8, 2010.
    • View In Article
21. Busse WW, Lemanske RF. Expert Panel Report 3: moving forward to improve asthma care. J Allergy Clin Immunol. 2007;120:1012–1014
    • View In Article
    • Full Text
    • Full-Text PDF (61 KB)
    • CrossRef
22. Ait-Khaled N, Enarson D. Management of asthma guidelines: guide for low income countries. IUATLD. Frankfurt am Main, Moskau, Senwald, Wien: pmi-Verl. Gruppe; 1996;
    • View In Article
23. Aït-Khaled N, Enarson DA, Chen-Yuan C, Marks G, Bissell K. Management of asthma: a guide to the essentials of good clinical practice. 3rd ed.. Paris: International Union Against Tuberculosis and Lung Disease; 2008;
    • View In Article
24. Roche N, Morel H, Martel P, Godard P. Clinical practice guidelines: medical follow-up of patients with asthma—adults and adolescents. Respir Med. 2005;99:793–815
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (403 KB)
    • CrossRef
25. Li J, Oppenheimer J, Bernstein IL, Nicklas RA, Khan DA, Blessing-Moore J, et al. Attaining optimal asthma control: a practice parameter. J Allergy Clin Immunol. 2005;116(5):S3–11
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (145 KB)
    • CrossRef
26. Cruz AA, Bousquet PJ. The unbearable cost of severe asthma in underprivileged populations. Allergy. 2009;64:319–321
    • View In Article
    • CrossRef
27. Franco R, Nascimento HF, Cruz AA, Santos AC, Souza-Machado C, Ponte EV, et al. The economic impact of severe asthma to low-income families. Allergy. 2009;64:478–483
    • View In Article
    • CrossRef
28. Chung KF, Godard P, Adelroth E, Ayres J, Barnes N, Barnes P, et al. 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. 1999;13:1198–1208
    • View In Article
    • MEDLINE
    • CrossRef
29. Mendis S, Fukino K, Cameron A, Laing R, Filipe A, Khatib O, et al. The availability and affordability of selected essential medicines for chronic diseases in six low- and middle-income countries. Bull World Health Organ. 2007;85:279–288
    • View In Article
    • MEDLINE
    • CrossRef
30. Cameron A, Ewen M, Ross-Degnan D, Ball D, Laing R. Medicine prices, availability, and affordability in 36 developing and middle-income countries: a secondary analysis. Lancet. 2009;373:240–249
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (200 KB)
    • CrossRef
31. Camacho M, Nogales M, Manjon R, Del Granado M, Pio A, Ottmani S. Results of PAL feasibility test in primary health care facilities in four regions of Bolivia. Int J Tuberc Lung Dis. 2007;11:1246–1252
    • View In Article
32. English RG, Bateman ED, Zwarenstein MF, Fairall LR, Bheekie A, Bachmann MO, et al. Development of a South African integrated syndromic respiratory disease guideline for primary care. Prim Care Respir J. 2008;17:156–163
    • View In Article
    • CrossRef
33. World Health Organization. 2008-2013 Action plan for the global strategy for the preventionand control of non communicable diseases. Prevent and control cardiovascular diseases, cancers, chronic respiratory diseases, diabetes. 2008. Available at: http://www.who.int/nmh/Actionplan-PC-NCD-2008.pdf. Accessed April 2, 2009.
    • View In Article
34. World Health Organization. WHO Model List of Essential Medicines. 15th list, March 2007. Available at: http://www.who.int/medicines. Accessed April 2, 2009.
    • View In Article
35. Hendeles L, Colice GL, Meyer RJ. Withdrawal of albuterol inhalers containing chlorofluorocarbon propellants. N Engl J Med. 2007;356:1344–1351
    • View In Article
    • CrossRef
36. Woodcock A. The Montreal Protocol: getting over the finishing line?. Lancet. 2009;373:705–706
    • View In Article
    • Full Text
    • Full-Text PDF (64 KB)
    • CrossRef
37. US guidance: metered dose inhaler (MDI) and dry powder inhaler (DPI) drug products—chemistry, manufacturing, and control documentaion. Draft guidance. 1998. Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance/ucm070573.pdf. Accessed August 28, 2010.
    • View In Article
38. US guidance: nasal spray and inhalation solution, suspension, and spray drug products—chemistry, nanufacturing, and control documentation. 2002. Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance/ucm070575.pdf. Accessed August 28, 2010.
    • View In Article
39. EMEA/European guidance: points to consideron the requirements for clinical documentation for orally inhaled products (OIP). 2004. Available at: http://www.emea.europa.eu/pdfs/human/ewp/415100en.pdf. Accessed December 9, 2009.
    • View In Article
40. Canadian guidance: pharmaceutical quality of inhalation and nasal products. 2006. Available at: http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/prodpharma/inhalationnas-eng.pdf. Accessed December 9, 2009.
    • View In Article
41. APM Health Europe. Novartis recalls asthma and COPD inhaler Foradil Certihaler in Germany and Switzerland. 2006. Available at: http://www.apmhealtheurope.com/story.php?mots=CERTIHALER&searchScope=1&searchType=0&numero=1282&ctx=ad9516ae784b5f9a5d4fc81eb56e2326. Accessed January 27, 2006.
    • View In Article
42. Otto A. Repeated recalls: is FDA's inspection system working? Pharmacy Today. 2000. Available at: http://www.medscape.com/viewarticle/406761. Accessed August 23, 2010.
    • View In Article
43. Public Citizen. Request to HHS to investigate charges against Schering-Plough for possibly knowingly shipping millions of asthma drug inhaler that may not have contained any active ingredient (HRG publication #1559). 2001. Available at: http://www.citizen.org/publications/release.cfm?ID=6762. Accessed September 9, 2010.
    • View In Article
44. Haahtela T, Klaukka T, Koskela K, Erhola M, Laitinen LA Working Group of the Asthma Programme in Finland 1994-2004. Asthma programme in Finland: a community problem needs community solutions. Thorax. 2001;56:806–814
    • View In Article
    • MEDLINE
    • CrossRef
45. Haahtela T, Tuomisto LE, Pietinalho A, Klaukka T, Erhola M, Kaila M, et al. A 10 year asthma programme in Finland: major change for the better. Thorax. 2006;61:663–670
    • View In Article
    • MEDLINE
    • CrossRef
46. Teles-de-Araujo A. Relatório do Observatório Nacional de Doenças Respiratórias (National Observatoire Respiratory Diseases Report). Rev Port Imunoalergologia. 2007;15:121–131
    • View In Article
47. Gaspar A, Morais-Almeida M, Nunes C. Epidemiologia da asma grave. Rev Port Imunoallergologia. 2006;14(suppl 2):27–41
    • View In Article
48. Tual S, Godard P, Piau JP, Bousquet J, Annesi-Maesano I. Asthma-related mortality in France, 1980-2005: decline since the last decade. Allergy. 2008;63:621–623
    • View In Article
    • CrossRef
49. Evans R, Gergen PJ, Mitchell H, Kattan M, Kercsmar C, Crain E, et al. A randomized clinical trial to reduce asthma morbidity among inner-city children: results of the National Cooperative Inner-City Asthma Study. J Pediatr. 1999;135:332–338
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (181 KB)
    • CrossRef
50. Fischer GB, Camargos PA, Mocelin HT. The burden of asthma in children: a Latin American perspective. Paediatr Respir Rev. 2005;6:8–13
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (182 KB)
51. Franco R, Santos AC, do Nascimento HF, Souza-Machado C, Ponte E, Souza-Machado A, et al. Cost-effectiveness analysis of a state funded programme for control of severe asthma. BMC Public Health. 2007;7:82
    • View In Article
    • MEDLINE
    • CrossRef
52. Ait-Khaled N, Enarson DA, Bencharif N, Boulahdib F, Camara LM, Dagli E, et al. Treatment outcome of asthma after one year follow-up in health centres of several developing countries. Int J Tuberc Lung Dis. 2006;10:911–916
    • View In Article
    • MEDLINE
53. Nathan RA, Sorkness CA, Kosinski M, Schatz M, Li JT, Marcus P, et al. Development of the asthma control test: a survey for assessing asthma control. J Allergy Clin Immunol. 2004;113:59–65
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (90 KB)
    • CrossRef
54. Juniper EF, O'Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of a questionnaire to measure asthma control. Eur Respir J. 1999;14:902–907
    • View In Article
    • MEDLINE
    • CrossRef
55. Peters D, Chen C, Markson LE, Allen-Ramey FC, Vollmer WM. Using an asthma control questionnaire and administrative data to predict health-care utilization. Chest. 2006;129:918–924
    • View In Article
    • MEDLINE
    • CrossRef
56. Thomas M, Gruffydd-Jones K, Stonham C, Ward S, Macfarlane TV. Assessing asthma control in routine clinical practice: use of the Royal College of Physicians “3 Questions”. Prim Care Respir J. 2009;18:83–88
    • View In Article
57. LeBlanc A, Robichaud P, Lacasse Y, Boulet LP. Quantification of asthma control: validation of the Asthma Control Scoring System. Allergy. 2007;62:120–125
    • View In Article
    • MEDLINE
58. Sullivan SD, Wenzel SE, Bresnahan BW, Zheng B, Lee JH, Pritchard M, et al. Association of control and risk of severe asthma-related events in severe or difficult-to-treat asthma patients. Allergy. 2007;62:655–660
    • View In Article
    • MEDLINE
    • CrossRef
59. Brand PL, Baraldi E, Bisgaard H, Boner AL, Castro-Rodriguez JA, Custovic A, et al. Definition, assessment and treatment of wheezing disorders in preschool children: an evidence-based approach. Eur Respir J. 2008;32:1096–1110
    • View In Article
    • CrossRef
60. Reddel H, Ware S, Marks G, Salome C, Jenkins C, Woolcock A. Differences between asthma exacerbations and poor asthma control [published erratum appears in Lancet 1999;353:758]. Lancet. 1999;353:364–369
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (84 KB)
    • CrossRef
61. Burney P, Potts J, Aït-Khaled N, Sepulveda RM, Zidouni N, Benali R. A multinational study of treatment failures in asthma management. Int J Tuberc Lung Dis. 2008;12:13–18
    • View In Article
62. Thomson NC, Chaudhuri R. Asthma in smokers: challenges and opportunities. Curr Opin Pulm Med. 2009;15:39–45
    • View In Article
63. American Lung Association Asthma Clinical Research CentersMastronarde JG, Anthonisen NR, Castro M, Holbrook JT, Leone FT, et al. Efficacy of esomeprazole for treatment of poorly controlled asthma. N Engl J Med. 2009;360:1487–1499
    • View In Article
    • CrossRef
64. Ito K, Chung KF, Adcock IM. Update on glucocorticoid action and resistance. J Allergy Clin Immunol. 2006;117:522–543
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (584 KB)
    • CrossRef
65. Bhavsar P, Hew M, Khorasani N, Torrego A, Barnes PJ, Adcock I, et al. Relative corticosteroid insensitivity of alveolar macrophages in severe asthma compared with non-severe asthma. Thorax. 2008;63:784–790
    • View In Article
    • CrossRef
66. Adcock IM, Ford PA, Bhavsar P, Ahmad T, Chung KF. Steroid resistance in asthma: mechanisms and treatment options. Curr Allergy Asthma Rep. 2008;8:171–178
    • View In Article
    • CrossRef
67. World Health Organization. The World Health Report 2008—primary health care: now more than ever. 2008. Available at: http://www.who.int/whr/2008/en/index.html. Accessed April 2, 2009.
    • View In Article
68. Currie GP, Douglas JG, Heaney LG. Difficult to treat asthma in adults. BMJ. 2009;338:b494
    • View In Article
    • CrossRef
69. Brasier AR, Victor S, Boetticher G, Ju H, Lee C, Bleecker ER, et al. Molecular phenotyping of severe asthma using pattern recognition of bronchoalveolar lavage-derived cytokines. J Allergy Clin Immunol. 2008;121:30–37e6
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (1592 KB)
    • CrossRef
70. Miller MK, Johnson C, Miller DP, Deniz Y, Bleecker ER, Wenzel SE TENOR Study Group. Severity assessment in asthma: an evolving concept. J Allergy Clin Immunol. 2005;116:990–995
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (186 KB)
    • CrossRef
71. Haldar P, Pavord ID, Shaw DE, Berry MA, Thomas M, Brightling CE, et al. Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med. 2008;178:218–224
    • View In Article
    • CrossRef
72. ten Brinke A, Zwinderman AH, Sterk PJ, Rabe KF, Bel EH. Factors associated with persistent airflow limitation in severe asthma. Am J Respir Crit Care Med. 2001;164:744–748
    • View In Article
73. Moore WC, Meyers DA, Wenzel SE, Teague WG, Li H, Li X, et al. Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am J Respir Crit Care Med. 2010;181:315–323
    • View In Article
    • CrossRef
74. Hammad H, Lambrecht BN. Dendritic cells and epithelial cells: linking innate and adaptive immunity in asthma. Nat Rev Immunol. 2008;8:193–204
    • View In Article
75. Bousquet J, Jeffery PK, Busse WW, Johnson M, Vignola AM. Asthma: from bronchoconstriction to airways inflammation and remodeling. Am J Respir Crit Care Med. 2000;161:1720–1745
    • View In Article
76. Folli C, Descalzi D, Scordamaglia F, Riccio AM, Gamalero C, Canonica GW. New insights into airway remodelling in asthma and its possible modulation. Curr Opin Allergy Clin Immunol. 2008;8:367–375
    • View In Article
    • CrossRef
77. Kraft M. The distal airways: are they important in asthma?. Eur Respir J. 1999;14:1403–1417
    • View In Article
    • MEDLINE
    • CrossRef
78. Holgate ST. Epithelium dysfunction in asthma. J Allergy Clin Immunol. 2007;120:1233-44; quiz 5-6
    • View In Article
79. Siddiqui S, Gupta S, Cruse G, Haldar P, Entwisle J, Mcdonald S, et al. Airway wall geometry in asthma and nonasthmatic eosinophilic bronchitis. Allergy. 2009;64:951–958
    • View In Article
    • CrossRef
80. Anderson GP. Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease. Lancet. 2008;372:1107–1119
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (217 KB)
    • CrossRef
81. Ponte EV, Franco R, Nascimento HF, Souza-Machado A, Cunha S, Barreto ML, et al. Lack of control of severe asthma is associated with co-existence of moderate-to-severe rhinitis. Allergy. 2008;63:564–569
    • View In Article
    • CrossRef
82. Bresciani M, Paradis L, Des Roches A, Vernhet H, Vachier I, Godard P, et al. Rhinosinusitis in severe asthma. J Allergy Clin Immunol. 2001;107:73–80
    • View In Article
    • Abstract
    • Full-Text PDF (171 KB)
    • CrossRef
83. ten Brinke A, Grootendorst DC, Schmidt JT, De Bruïne FT, van Buchem MA, Sterk PJ, et al. Chronic sinusitis in severe asthma is related to sputum eosinophilia. J Allergy Clin Immunol. 2002;109:621–626
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (106 KB)
    • CrossRef
84. Asher MI, Montefort S, Björkstén B, Lai CK, Strachan DP, Weiland SK, et al. Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys. Lancet. 2006;368:733–743
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (2996 KB)
    • CrossRef
85. Tager IB, Ngo L, Hanrahan JP. Maternal smoking during pregnancy: effects on lung function during the first 18 months of life. Am J Respir Crit Care Med. 1995;152:977–983
    • View In Article
86. Lodrup Carlsen KC, Jaakkola JJ, Nafstad P, Carlsen KH. In utero exposure to cigarette smoking influences lung function at birth. Eur Respir J. 1997;10:1774–1779
    • View In Article
    • MEDLINE
    • CrossRef
87. Gouveia N, Bremner SA, Novaes HM. Association between ambient air pollution and birth weight in Sao Paulo. Brazil. J Epidemiol Community Health. 2004;58:11–17
    • View In Article
88. Chinn S, Jarvis D, Luczynska CM, Ackermann-Liebrich U, Antó JM, Cerveri I, et al. An increase in bronchial responsiveness is associated with continuing or restarting smoking. Am J Respir Crit Care Med. 2005;172:956–961
    • View In Article
    • CrossRef
89. Rusconi F, Galassi C, Forastiere F, Bellasio M, De Sario M, Ciccone G, et al. Maternal complications and procedures in pregnancy and at birth and wheezing phenotypes in children. Am J Respir Crit Care Med. 2007;175:16–21
    • View In Article
    • CrossRef
90. Gern JE, Brooks GD, Meyer P, Chang A, Shen K, Evans MD, et al. Bidirectional interactions between viral respiratory illnesses and cytokine responses in the first year of life. J Allergy Clin Immunol. 2006;117:72–78
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (191 KB)
    • CrossRef
91. Jackson DJ, Gangnon RE, Evans MD, Roberg KA, Anderson EL, Pappas TE, et al. Wheezing rhinovirus illnesses in early life predict asthma development in high-risk children. Am J Respir Crit Care Med. 2008;178:667–672
    • View In Article
    • CrossRef
92. Lowe LA, Simpson A, Woodcock A, Morris J, Murray CS, Custovic A NAC Manchester Asthma and Allergy Study Group. Wheeze phenotypes and lung function in preschool children. Am J Respir Crit Care Med. 2005;171:231–237
    • View In Article
    • CrossRef
93. Morgan WJ, Stern DA, Sherrill DL, Guerra S, Holberg CJ, Guilbert TW, et al. Outcome of asthma and wheezing in the first 6 years of life: follow-up through adolescence. Am J Respir Crit Care Med. 2005;172:1253–1258
    • View In Article
    • CrossRef
94. Bush A. How early do airway inflammation and remodeling occur?. Allergol Int. 2008;57:11–19
    • View In Article
    • CrossRef
95. Barbato A, Turato G, Baraldo S, Bazzan E, Calabrese F, Tura M, et al. Airway inflammation in childhood asthma. Am J Respir Crit Care Med. 2003;168:798–803
    • View In Article
    • CrossRef
96. Turato G, Barbato A, Baraldo S, Zanin ME, Bazzan E, Lokar-Oliani K, et al. Nonatopic children with multitrigger wheezing have airway pathology comparable to atopic asthma. Am J Respir Crit Care Med. 2008;178:476–482
    • View In Article
    • CrossRef
97. Saglani S, Payne DN, Zhu J, Wang Z, Nicholson AG, Bush A, et al. Early detection of airway wall remodeling and eosinophilic inflammation in preschool wheezers. Am J Respir Crit Care Med. 2007;176:858–864
    • View In Article
    • CrossRef
98. Bush A. COPD: a pediatric disease. COPD. 2008;5:53–67
    • View In Article
    • CrossRef
99. Long-term effects of budesonide or nedocromil in children with asthma. The Childhood Asthma Management Program Research Group. N Engl J Med. 2000;343:1054–1063
    • View In Article
    • MEDLINE
    • CrossRef
100. Castro-Rodriguez JA, Holberg CJ, Wright AL, Martinez FD. A clinical index to define risk of asthma in young children with recurrent wheezing. Am J Respir Crit Care Med. 2000;162(4 Pt 1):1403–1406
     • View In Article
101. Guilbert TW, Morgan WJ, Krawiec M, Lemanske RF, Sorkness C, Szefler SJ, et al. The Prevention of Early Asthma in Kids study: design, rationale and methods for the Childhood Asthma Research and Education network. Control Clin Trials. 2004;25:286–310
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (781 KB)
     • CrossRef
102. Devulapalli CS, Carlsen KC, Håland G, Munthe-Kaas MC, Pettersen M, Mowinckel P, et al. Severity of obstructive airways disease by age 2 years predicts asthma at 10 years of age. Thorax. 2008;63:8–13
     • View In Article
     • CrossRef
103. van-Essen-Zandvliet EE. Long-term intervention in childhood asthma: the Dutch study results. Dutch Chronic Nonspecific Lung Disease Study Group. Monaldi Arch Chest Dis. 1995;50:201–207
     • View In Article
     • MEDLINE
104. van-Essen-Zandvliet EE, Hughes MD, Waalkens HJ, Duiverman EJ, Pocock SJ, Kerrebijn KF. Effects of 22 months of treatment with inhaled corticosteroids and/or beta-2-agonists on lung function, airway responsiveness, and symptoms in children with asthma. The Dutch Chronic Non-specific Lung Disease Study Group. Am Rev Respir Dis. 1992;146:547–554
     • View In Article
     • MEDLINE
105. Guilbert TW, Morgan WJ, Zeiger RS, Mauger DT, Boehmer SJ, Szefler SJ, et al. Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med. 2006;354:1985–1997
     • View In Article
     • CrossRef
106. Murray CS, Woodcock A, Langley SJ, Morris J, Custovic A IFWIN study team. Secondary prevention of asthma by the use of Inhaled Fluticasone propionate in Wheezy INfants (IFWIN): double-blind, randomised, controlled study. Lancet. 2006;368:754–762
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (149 KB)
     • CrossRef
107. Lang A, Carlsen KH, Haaland G, Devulapalli CS, Munthe-Kaas M, Mowinckel P, et al. Severe asthma in childhood: assessed in 10 year olds in a birth cohort study. Allergy. 2008;63:1054–1060
     • View In Article
     • CrossRef
108. Dolan CM, Fraher KE, Bleecker ER, Borish L, Chipps B, Hayden ML, 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;92:32–39
     • View In Article
     • Abstract
     • Full-Text PDF (199 KB)
     • CrossRef
109. Drazen JM, O'Byrne PM. Risks of long-acting beta-agonists in achieving asthma control. N Engl J Med. 2009;360:1671–1672
     • View In Article
     • CrossRef
110. Bacharier LB, Boner A, Carlsen KH, Eigenmann PA, Frischer T, Götz M, et al. Diagnosis and treatment of asthma in childhood: a PRACTALL consensus report. Allergy. 2008;63:5–34
     • View In Article
     • CrossRef