Review and Feature Article
Severe Asthma in Children

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Severe asthma in children is characterized by sustained symptoms despite treatment with high doses of inhaled corticosteroids or oral corticosteroids. Children with severe asthma may fall into 2 categories, difficult-to-treat asthma or severe therapy-resistant asthma. Difficult-to-treat asthma is defined as poor control due to an incorrect diagnosis or comorbidities, or poor adherence due to adverse psychological or environmental factors. In contrast, treatment resistant is defined as difficult asthma despite management of these factors. It is increasingly recognized that severe asthma is a highly heterogeneous disorder associated with a number of clinical and inflammatory phenotypes that have been described in children with severe asthma. Guideline-based drug therapy of severe childhood asthma is based primarily on extrapolated data from adult studies. The recommendation is that children with severe asthma be treated with higher-dose inhaled or oral corticosteroids combined with long-acting β-agonists and other add-on therapies, such as antileukotrienes and methylxanthines. It is important to identify and address the influences that make asthma difficult to control, including reviewing the diagnosis and removing causal or aggravating factors. Better definition of the phenotypes and better targeting of therapy based upon individual patient phenotypes is likely to improve asthma treatment in the future.

Section snippets

Severe Asthma in Children Is Different than Adult Disease

Extrapolating adult severity classifications to children is difficult for a number of reasons. Adults with asthma are more likely to exhibit a persistent pattern, whereas children may have a pattern of rapidly evolving, frequent, and often severe exacerbations. Children have severe exacerbations triggered by viral infections and/or allergen exposure that can result in health care utilization but then often remain asymptomatic between these episodes.10, 11 Phenotypes of severe asthma in children

Epidemiology of Severe Asthma

Epidemiologic studies have described risk factors for severe asthma and airway hyperresponsiveness. Many children with severe asthma present when school age (range, 6-11 years); however, they report the onset of asthma symptoms earlier in childhood (first 3 years of life) than children with mild-to-moderate asthma (5 years mean).3, 29 Another risk factor for asthma and severe airway hyperresponsiveness may be lower lung function present shortly after birth. Infants with the lowest pulmonary

Severe Asthma Definitions

Although several definitions of “severe asthma” have been proposed, no single definition has gained universal acceptance due to the complex nature of the disease and the lack of validated criterion standards for diagnosis. To further complicate matters, “asthma” itself is a highly heterogeneous condition that remains poorly understood in children. In a recent review of large cohorts of school-age children with asthma, 122 publications yielded 60 different operational definitions of asthma,

Heterogeneity of Severe Asthma in Children

It is increasingly recognized that severe asthma is a highly heterogeneous disorder associated with a number of clinical and inflammatory phenotypes that can be assessed through detailed analysis of induced sputum, bronchoalveolar lavage, or endobronchial biopsy.44, 45, 46, 47 Although this research is incomplete, particularly in children with severe asthma, 3 phenotypes of airway inflammation have been described: (1) eosinophilic inflammation,48, 49 (2) paucigranulocytic inflammation,48, 49

Differential Diagnosis

Several diseases that mimic asthma should be considered during the evaluation of a child with severe asthma (Table II). These include the following: structural airway abnormality, intrabronchial obstruction, aspiration, gastroesophageal reflux with or without recurrent microaspiration, cystic fibrosis, ciliary dyskinesia, immune dysfunction, bronchiectasis, pulmonary edema, lung disease of prematurity, bronchiolitis obliterans syndrome, and hypersensitivity pneumonitis.

Laboratory, Pulmonary Function, Bronchoscopic Evaluations

Evaluation of a child with severe asthma may include physiological measurements, such as pre- and postbronchodilator spirometry and body plethysmography. It can include assessment of airway inflammation, such as FENO, sputum eosinophils (research tool), bronchoscopy with bronchoalveolar lavage, and bronchial biopsy; and tests for allergic sensitization, such as specific allergen IgE or aeroallergen skin prick tests, or additional evaluation for comorbidities or diseases that mimic asthma (

Comorbidities

Severe asthma in children is associated with several comorbidities, such as obesity, gastroesophageal reflux, dysfunctional breathing, and mental disorders, that may exacerbate the severity of asthma symptoms. Evaluation for these disorders should be considered (Table II).

Evaluation

Analysis of recent research on severe asthma indicates that a structured approach to evaluation and therapy is important.46, 100 First, the child should be assessed for disorders that may mimic asthma (see the Differential Diagnosis section). In 37 young children with severe wheezing unresponsive to therapy, Saglani et al101 found structural abnormalities on bronchoscopy in 36% and evidence of gastroesophageal reflux (an abnormal pH study or lipid-laden macrophages on bronchoalveolar lavage) in

Management, Treatment, Conventional Therapy, Controllers

At present, guideline-based drug therapy of severe childhood asthma is based primarily on extrapolated data from adult studies. The recommendation is that children with severe asthma be treated with higher-dose ICS or oral corticosteroids combined with long-acting β-agonists (LABA) and other add-on therapies.27, 97, 104 Results of some studies showed no evidence of secondary prevention of symptoms and prevention of a decline of lung function,105, 106, 107 whereas, results of other studies

Specific Allergen Immunotherapy

Specific allergen immunotherapy has been demonstrated to have beneficial effects with the management of childhood asthma, including effects on symptom control, medication use, and airway hyperresponsiveness.132 A recent meta-analysis that examined the efficacy of allergen-specific immunotherapy concluded that there is moderate-strength evidence that subcutaneous immunotherapy improves asthma symptoms and high-strength evidence that sublingual immunotherapy improves asthma symptoms.133 However,

Emerging Therapies

Other novel medications for asthma have been studied with adults, and most are considered experimental with children.

Patient Education and Lifestyle Modification

Both national and international asthma guidelines strongly recommend structured asthma education.97, 104 A good dialogue between patients and care providers is encouraged. Moreover, patients may have different ideas from physicians regarding symptom control as well as strong lay beliefs about medications and their adverse effects, which should be addressed. A balance among the degree of asthma control, medication adverse effects, and quality of life should be established. A structured

Conclusions

Although knowledge of asthma and its associated mechanisms has increased substantially over the past decades, significant gaps remain about the determinants of severe asthma in children. It is not clear how the different phenotypes of severe asthma change across time, nor is it clear if these changes are modifiable with appropriate therapy. It is important to identify and address the influences that make asthma difficult to control, including reviewing the diagnosis and the removal of causal or

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    No funding was received for this work.

    Conflicts of interest: Disclosure of potential conflict of interest: T. Guilbert is on the American Board of Pediatrics and the Pediatric Pulmonary Subboard; has received consultancy fees from Teva, GlaxoSmithKline, and Regeneron Pharmaceuticals; has received research support from the Centers for Disease Control, Department of Health and Human Services (DHHS FAB 20166; T72 MC00008-20-00), National Institutes of Health (NIH), University of Wisconsin Madison Medical and Education Research Committee, Teva, GlaxoSmithKline/Development Limited, CF Foundation Therapeutics, Roche/Genentech, and the NIH; receives royalties from UpToDate; and has received payment for development of educational presentations from Teva. L. B. Bacharier has received consultancy fees from Aerocrine, GlaxoSmithKline, Genentech/Novartis, Merck, Schering, Cephalon, and DBV Technologies; has received research support from the National Heart, Lung, and Blood Institute (NHLBI)/NIH AsthmaNet (NHLBI U10 HL098090; U10 HL109168; P01 HL070831); has received lecture fees from Aerocrine, AstraZeneca, Genentech/Novartis, GlaxoSmithKline, Merck, and Schering. A. M. Fitzpatrick has received research support from the National Institutes of Health, NHLBI (R01 NR012021) and National Institute of Nursing Research (R01 NR013700); has received consultancy fees from MedImmune, Merck Scientific Advisory Board, GlaxoSmithKline Advisory Board, Genentech, and Boehringer Ingelheim.

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