Millions of children will fail to live up to their potential if asthma is not addressed.

ASTHMA RESEARCH

The focus of asthma research in the past few decades has been prevention and treatment. Research in prevention has aimed to identify risk and protective factors that may determine either the beginning of the disease (primary causes) or may provoke attacks in those who already have the condition (secondary causes). Research in treatment has sought to identify the most effective drug therapy and therapeutic targets.

An interdisciplinary approach is the most likely to open up new avenues of cutting-edge research.

Population-based studies of asthma

The two main research approaches used are cross-sectional prevalence studies involving subjects from many countries, such as ISAAC, and the European Community Respiratory Health Survey (ECRHS) in adults; and longitudinal cohort studies, in which individuals are followed for long periods of time, such as Phases II and III of the ECRHS and birth cohort studies ongoing in many countries, primarily in the developed world.

Studying the mechanics of asthma

Much clinical and basic science research has been dedicated to improve our understanding both of changes in the lung and how they influence its mechanics in asthma; and of the alterations in the immunological pathways that cause inflammation, bronchial constriction and altered mucus secretion, which may end up in irreversible lung damage.

Understanding the role of the immune system and other issues

Research has identified numerous newly discovered molecules secreted by cells either to produce inflammation or to communicate with other cells involved in this process. However, the mechanisms by which the immunological system may shift from a well-regulated situation to a dysfunctional one (as occurs in allergy) have yet to be established. Furthermore, the role of viruses or bacteria, which can mutate with time, is still not definitely known. It is suspected that the immune system may be "programmed" during fetal and/or very early postnatal development. The potential importance of the environment of the developing fetus is being explored.

Combining drugs: a milestone in asthma treatment

Safe and effective drugs capable of preventing asthma attacks and controlling symptoms during exacerbations are essential to effective clinical management of asthma. Inhaled corticosteroids are very effective to reduce bronchial inflammation, and their adverse effects have been diminished in the past years both by using safer molecules and by improving their formulation. Inhaled bronchodilators, such as salbutamol, have been used as efficient bronchodilators for asthma since the 1960s. The discovery of the synergistic effects of adding these drugs to inhaled corticosteroids was a milestone in the treatment of asthma 15 years ago.

Only two new drugs in past 15 years

Since then, only two new and more specific drugs have become commercially available: antagonists to leukotriene (an immunologic mediator) and monoclonal antibodies against

immunoglobulin E (a key molecule in the allergic pathway). The former can be used as preventer medication on a regular basis, but the latter are reserved for very severe allergic asthma. Pharmaceutical companies have dedicated considerable resources to finding new therapeutic targets among the newly discovered molecular mediators of asthma and allergy, with very limited success. Research in asthma treatment will probably continue in this direction in the years to come, but significant breakthroughs are considered to be unlikely.

Interdisciplinary approach holds most promise

Perhaps the most promising new direction for asthma research in the 21st century is the development of a truly interdisciplinary approach that integrates the usually separate worlds of epidemiology, social science and biomedical and clinical research. Traditionally these disciplines have conducted their research in relative isolation, a situation that has distinct disadvantages. In particular: (i) many animal models of asthma are only partially applicable to human populations; (ii) clinical studies are generally not well equipped to determine the causal exposures of primary causation; and (iii) epidemiological studies often don’t fully acknowledge the complexity of the biological responses involved.

Findings in high-income countries do not apply to all

Another shortcoming has been the common assumption that findings in high-income countries can be extrapolated to the rest of the world. It has taken international collaborations, such as ISAAC, to show that, for example, the strong associations between allergy and asthma symptoms, which have been repeatedly observed in high-income countries, are not so evident in low- and middle-income countries.

Non-allergic asthma more common in low- and middle-income countries

Overemphasis on allergen exposure as the “causal” factor of asthma, as well as the lack of appreciation of the variation in types of asthma in many epidemiological studies, has guided biomedical and clinical research into studying (almost exclusively) allergic mechanisms and allergy-specific treatment options, with very little consideration of other potentially relevant biological pathways. For example, corticosteroid treatment seems to be less effective in asthma phenotypes that do not involve allergic mechanisms and subsequent non-eosinophilic airway inflammation, despite these types of asthma being common in the general population, and probably the most common types in low- and middle-income countries.

Addressing the complex interplay of factors

Considering the complex interplay between environmental exposures, genetic susceptibility, immunological mechanisms, as well as social and cultural factors involved in asthma development – and indeed most noncommunicable diseases – an interdisciplinary approach that brings together expertise from each of these disciplines is most desirable. This type of approach is the most likely to open up new avenues of cuttingedge research, yielding greater explanatory power, more efficient use of research funding and more efficient translation into disease prevention.

-Luis García-Marcos, Neil Pearce, David Strachan

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