Asthma treatment and asthma prevention: A tale of 2 parallel pathways

doi:10.1016/j.jaci.2006.10.020

Journal of Allergy and Clinical Immunology

Volume 119, Issue 1, January 2007, Pages 30-33

https://doi.org/10.1016/j.jaci.2006.10.020 Get rights and content

Three recent clinical trials used different study designs to test the hypothesis that early introduction of inhaled corticosteroids in infants and young children at high risk for the development of asthma could change the natural course of the disease. All 3 trials reached the same conclusion: treatment requirement, symptom frequency while off treatment, and lung function did not differ between children receiving active drug or placebo, with outcomes measured 2 to 4 years after randomization. These findings challenge the concept that the inflammatory processes that cause asthma symptoms and are responsive to inhaled corticosteroids are also responsible for the chronic changes in airway structure and function that are believed to predispose to the development of persistent asthma. This conclusion is supported by studies showing that bronchial hyperresponsiveness, independent of current asthma symptoms, is associated with subsequent deficits in airway function growth during childhood. Successful strategies for the prevention of asthma will require a better understanding of the genetic, environmental, and developmental factors that predispose toward inappropriate responses to airway injury. Abnormal airway remodeling and persistent dysregulation of airway tone might be the final common pathway for different disease mechanisms, and this might explain the heterogeneity of clinical phenotypic syndromes that go under the common label of “asthma.”

Section snippets

Airway inflammation and airway remodeling: cause and effect?

Concomitantly with these paradigm-shifting findings, epidemiologic and clinical studies provided strong evidence suggesting that persistent asthma was associated with both deficits in lung function growth⁷ and chronic pathologic changes in the airways. These changes are characterized by an increase in airway smooth muscle mass, subepithelial fibrosis with thickening of the lamina reticularis, mucus gland hyperplasia, and increased vascularity.⁸ Although the intensity of these features of asthma

Lung function growth and decline in asthma

Perhaps the greatest challenge to the concept that ICSs might prevent the long-term effects of asthma on airway anatomy and physiology came from longitudinal studies of lung function growth and decrease in asthma. Cohort studies from general populations reproducibly concluded that in children with persistent asthma symptoms, most deficits in lung function growth have already occurred by age 6 to 9 years,¹⁴ with a modest further effect of asthma on lung function thereafter. Moreover, although

Inhaled corticosteroids and asthma prevention

A first such study in schoolchildren, the Childhood Asthma Management Program (CAMP) study,³ was among the initial studies funded by the NHLBI as part of the Asthma Networks. In the CAMP study approximately 1000 schoolchildren aged 5 to 12 years with mild-to-moderate asthma were randomized to daily treatment with budesonide, nedocromil, or placebo taken for a period of 4 to 6 years. The main outcome variable was postbronchodilator FEV₁. Two main results emerged from this study: first, no

Symptom-related inflammation is not responsible for deficits in lung function in asthma

Taken together, the data strongly suggest that ICSs, although very effective in controlling asthma symptoms, cannot block or reverse either the deficits in lung function observed in some patients with asthma or the changes in airway structure (presumably “airway remodeling”) that underlie these deficits.

One possible explanation for these unexpected findings is that deficits in airway function (and perhaps airway remodeling) in asthma occur in parallel to and are not the result of ICS-sensitive,

Conclusions: the next steps

The pioneering trials performed as part of the NHLBI Asthma Networks have quite conclusively shown that among children with asthma (or at risk for asthma) of different ages, controller therapy with ICSs is efficacious in controlling asthma symptoms but does not change the natural clinical course of the disease. These findings open a series of new, important, and still unaddressed issues in childhood asthma:

•
There is a pressing need to develop therapeutic modalities that, initiated even earlier

References (26)

R.H. Green et al.
Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial
Lancet
(2002)
L. Agertoft et al.
Effects of long-term treatment with an inhaled corticosteroid on growth and pulmonary function in asthmatic children
Respir Med
(1994)
P.M. O'Byrne et al.
Effects of early intervention with inhaled budesonide on lung function in newly diagnosed asthma
Chest
(2006)
C.S. Murray et al.
Secondary prevention of asthma by the use of Inhaled Fluticasone propionate in Wheezy INfants (IFWIN): double-blind, randomised, controlled study
Lancet
(2006)
L. Cohn et al.
Asthma: mechanisms of disease persistence and progression
Annu Rev Immunol
(2004)
J. Bousquet et al.
Eosinophilic inflammation in asthma
N Engl J Med
(1990)
The Childhood Asthma Management Program Research Group
Long-term effects of budesonide or nedocromil in children with asthma
N Engl J Med
(2000)
J.K. Sont et al.
Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment. The AMPUL Study Group
Am J Respir Crit Care Med
(1999)
A.D. Smith et al.
Use of exhaled nitric oxide measurements to guide treatment in chronic asthma
N Engl J Med
(2005)
S.T. Weiss et al.
Effects of asthma on pulmonary function in children. A longitudinal population-based study
Am Rev Respir Dis
(1992)

P.K. Jeffery

Remodeling and inflammation of bronchi in asthma and chronic obstructive pulmonary disease

Proc Am Thorac Soc

(2004)

R.J. Homer et al.

Airway remodeling in asthma: therapeutic implications of mechanisms

Physiology (Bethesda)

(2005)

A. Chetta et al.

Vascular component of airway remodeling in asthma is reduced by high dose of fluticasone

Am J Respir Crit Care Med

(2003)

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Asthma transition from childhood into adulthood
2017, The Lancet Respiratory Medicine
Citation Excerpt :
Childhood and adult asthma resemble a complex syndrome rather than a single disease and present with different phenotypes1,2 that lead to the recognised state of variable airway obstruction, which at times is not fully reversible or even fixed during the disease course.3 Presumably, however, variable airway obstruction is affected through diverse underlying pathophysiological processes adding further to the complexity of our pathophysiological understanding.1,4 These diverse underlying mechanisms could be used to further define asthma, which is known as an asthma endotype.
Asthma is the most prevalent chronic respiratory disease both in children and adults and resembles a complex syndrome rather than a single disease. Different methods have been developed to better characterise distinct asthma phenotypes in childhood and adulthood. In studies of adults, most phenotyping relies on biomaterials from the lower airways; however, this information is missing in paediatric studies because of restricted accessibility. Few patients show symptoms throughout childhood, adolescence, and adulthood. Risk factors for this might be genetics, family history of asthma and atopy, infections early in life, allergic diseases, and lung function deficits. In turn, a large proportion of children with asthma lose their symptoms during school age and adolescence. This improved prognosis, which might also reflect a better treatment response, is associated with being male and with milder and less allergic disease. Importantly, whether clinical remission of symptoms equals the disappearance of underlying pathology is unknown. In fact, airway hyper-responsiveness and airway inflammation might remain despite the absence of overt symptoms. Additionally, a new-onset of asthma symptoms is apparent in adulthood, especially in women and in the case of impaired lung function. However, many patients do not remember childhood symptoms, which might reflect relapse rather than true initiation. Both relapse and adult-onset of asthma symptoms have been associated with allergic disease and sensitisation in addition to airway hyper-responsiveness. Thus, asthma symptoms beginning in adults might have originated in childhood. Equivocally, persistence into, relapse, and new-onset of symptoms in adulthood have all been related to active smoking. However, underlying mechanisms for the associations remain unclear, and future asthma research should therefore integrate standardised molecular approaches in identical ways in both paediatric and adult populations and in longitudinal studies.
Noncontractile Functions of Airway Smooth Muscle
2014, Middleton's Allergy: Principles and Practice: Eighth Edition
Airway Smooth Muscle in Asthma. Just a Target for Bronchodilation?
2012, Clinics in Chest Medicine
Citation Excerpt :
Increases in sub-basement membrane collagen and alterations in epithelial cell morphology, both hallmarks of airway remodeling, were a consistent feature observed in the study by Grainge130 in response to inflammatory (allergen) and noninflammatory (methacholine) challenges. Thus, it may be that the structural changes that constitute remodeling are not a consequence of chronic persistent inflammation, as was previously thought, but rather the two processes develop along separate parallel pathways, which is a hypothesis put forward by Martinez in 2007.132 Not only ASM cells per se but also their products (eg, ECM proteins) contribute to the area of the muscle bundle.133
New insights into the natural history of asthma: Primary prevention on the horizon
2011, Journal of Allergy and Clinical Immunology
Citation Excerpt :
Remarkably, the proportion of EFDs was significantly lower in children treated with fluticasone that in those treated with placebo during the treatment period, but EFDs rapidly converged for the 2 groups during the observation period, as did the frequency of exacerbations and lung function. These results suggested that current anti-inflammatory therapy, although effective in preventing symptoms, does not change either the natural history of asthma45 or the progression of the structural changes occurring in the asthmatic airway. At least 2 other major studies in preschool children reached similar conclusions.46,47
Recent studies of the natural history of asthma have shifted attention toward viral respiratory tract illness in early life as a major risk factor associated with the development of the most persistent forms of the disease. Although early aeroallergen sensitization is strongly associated with chronic asthma, several trials in which single-aeroallergen exposure in pregnancy and early childhood was successfully accomplished and compared with sham avoidance have failed to show any decrease in asthma incidence. New evidence suggests that complex interactions occur between viral infection and aeroallergen sensitization in genetically susceptible subjects that trigger the immune responses and airway changes that are characteristic of persistent asthma. The finding that exposure to bacterial products among children raised on farms is associated with diminished asthma prevalence during the school years has now been replicated, and experimental studies have suggested that these effects are mediated by the activation of regulatory T cells in the airway. It is thus plausible to hypothesize that primary prevention of asthma could be attained through surrogate therapeutic interventions that activate similar mechanisms in young children at high risk for asthma.
Advancing asthma care: The glass is only half full!
2011, Journal of Allergy and Clinical Immunology
Over the past 20 years, there has been a concerted effort in the United States to reduce morbidity related to chronic disease, including asthma. Attention was initially directed toward asthma in response to the recognition that asthma mortality was increasing and that the burden of disease was significant. These efforts to address asthma mortality led to many new initiatives to develop clinical practice guidelines, implement the asthma guidelines into clinical practice, conduct research to fill the gaps in the guidelines, and continuously revise the asthma guidelines as more information became available. An assessment of our progress shows significant accomplishments in relation to reducing asthma mortality and hospitalizations. Consequently, we are now at a crossroads in asthma care. Although we have recognized some remarkable accomplishments in reducing asthma mortality and morbidity, the availability of new tools to monitor disease activity, including biomarkers and epigenetic markers, along with information technology systems to monitor asthma control hold some promise in identifying gaps in disease management. These advances should prompt the evolution of new strategies and new treatments to further reduce disease burden. It now becomes imperative to continue a focus on ways to further reduce the burden of asthma and prevent its onset.
Risk factors for bronchial hyperresponsiveness in teenagers differ with sex and atopic status
2011, Journal of Allergy and Clinical Immunology
Sex-related differences in bronchial hyperresponsiveness (BHR) have been reported in adolescents, but the mechanisms remain obscure.
To investigate the risk factors for BHR in the Raine Study, a community-based longitudinal birth cohort.
At 14 years of age, children underwent a respiratory assessment including a questionnaire, lung function testing, methacholine challenge, and determination of atopic status.
A total of 1779 children provided data for assessment, with 1510 completing lung function and methacholine challenge testing. Current asthma was present in 152 (10.4%), 762 (50.5%) were atopic, and 277 (18.6%) had BHR. BHR was more common in girls, whereas atopy was more common in boys, with no sex differences in asthma or current wheeze. Independent risk factors for BHR were being female (odds ratio [OR], 3.45; P < .001), atopy at 14 years (OR, 1.27; P = .004), and current asthma (OR, 2.15; P = .005). Better lung function was protective against BHR (forced expiratory flow between 25% and 75% of forced vital capacity/forced vital capacity, OR, 0.09; P < .001). Risk factors differed with sex and atopic status. Early-life factors were generally not independent risk factors for BHR at 14 years of age, with the exception of being smaller at birth in boys (birth length, OR, 6 × 10⁻⁹; P = .017) and maternal asthma in girls (OR, 1.84; P = .041). Current asthma was not a risk for BHR in nonatopic children.
Bronchial hyperresponsiveness was more common and more severe in girls. These differences could not be explained by differences in lung function or atopic status.

View all citing articles on Scopus

Supported by U10HL64307, P02HL67672, U10HL56177, and R01HL04029.

Disclosure of potential conflict of interest: F. D. Martinez has consultant arrangements with Pfizer, Genentech, and Merck and has received lecture fees from Merck and Genentech.

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Asthma diagnosis and treatmentAsthma treatment and asthma prevention: A tale of 2 parallel pathways

Section snippets

Airway inflammation and airway remodeling: cause and effect?

Lung function growth and decline in asthma

Inhaled corticosteroids and asthma prevention

Symptom-related inflammation is not responsible for deficits in lung function in asthma

Conclusions: the next steps

Lancet

Respir Med

Chest

Lancet

Asthma: mechanisms of disease persistence and progression

Annu Rev Immunol

Eosinophilic inflammation in asthma

N Engl J Med

Long-term effects of budesonide or nedocromil in children with asthma

N Engl J Med

Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment. The AMPUL Study Group

Am J Respir Crit Care Med

Use of exhaled nitric oxide measurements to guide treatment in chronic asthma

N Engl J Med

Effects of asthma on pulmonary function in children. A longitudinal population-based study

Am Rev Respir Dis

Remodeling and inflammation of bronchi in asthma and chronic obstructive pulmonary disease

Proc Am Thorac Soc

Airway remodeling in asthma: therapeutic implications of mechanisms

Physiology (Bethesda)

Vascular component of airway remodeling in asthma is reduced by high dose of fluticasone

Am J Respir Crit Care Med

Asthma diagnosis and treatment
Asthma treatment and asthma prevention: A tale of 2 parallel pathways