AJRCCM: 100-Year Anniversary. Focus on Asthma in Children and Adults

Asthma was a late comer to the Journal. Between 1917, when the Journal was created as American Review of Tuberculosis, and 1990, the Journal seldom published more than a handful of articles including the keyword “asthma” each year. Starting in 1990, there was a large increase in publications about asthma in the Journal, which has been publishing 50 to 200 articles per year about the disease ever since.

These changes are not surprising. Asthma was considered a rather rare disease until well into the 1970s. In Finland, for example, the prevalence of asthma changed little between the 1930s and 1960s, hovering between 0.02 and 0.08%. Between 1961 and 1989, however, prevalence increased 20-fold to 1.79% (1). Analogously, interest in research on the causes of these increases and on the pathogenesis of the disease also swelled and clearly influenced editorial choices of the Journal.

We identified the 50 most-cited articles in both the American Review of Respiratory Disease (the previous name of the Journal) and the American Journal of Respiratory and Critical Care Medicine, as it has been called since 1994, using Web of Science. A succinct analysis revealed that a majority of the papers were concentrated in four areas of interest that still today are at the center of the attention of the scientific community. Most articles cited below come from those two lists. It is not our intention to produce an exhaustive account of all meritorious papers published in the Journal in these four areas but simply to highlight the role that the Journal plays in channeling and directing major advances in asthma research worldwide.

Asthma Origins in Early Life

It is now well established that most cases of asthma have their roots in events occurring during the developing years. Yunginger and coworkers (2) assessed asthma encounters between 1964 and 1983 among most residents of Rochester, Minnesota using existing medical records and reported that incidence peaked in the preschool years and waned steadily thereafter. Subsequent reports from the Tucson birth cohort have confirmed these findings (3), and an asthma predictive index (4) was developed, which has been used in major clinical trials (5, 6) to identify young children at high risk for the disease. Birth cohorts also identified early allergic sensitization (7) and wheezing rhinovirus infections in infancy (8), which are also major triggers of asthma exacerbations later in life (9), as strong predictors of the subsequent development of asthma. On the basis of these findings, the possibility has been raised that prevention of wheezing lower respiratory illnesses in susceptible subjects could be a potential approach for the primary prevention of childhood asthma (10).

Asthma and the Environment: Risk and Protection

The Journal published landmark articles contributing to our understanding of the role of environmental factors in protection and risk for asthma. Particulate respirable air pollution was shown to significantly increase the risk for asthma attacks in the Seattle area (11) and for asthma hospitalizations in eight European cities (12). Reductions in peak expiratory flow and increases in symptoms of respiratory disease and asthma medication use were reported among patients with asthma exposed to elevated fine particulate pollution levels (13).

These results, added to a large number of similar studies worldwide, contributed to changes in environmental policy that have resulted in significant improvements in lung function growth in children (14).

Shortly after the reunification of Germany, von Mutius and coworkers (15) reported that the prevalence of current asthma and bronchial hyperresponsiveness was significantly higher in West Germany than in East Germany. Higher exposure to endotoxins in the home was also found to be protective against the development of allergic sensitization in children (16). These results opened a new field, namely, the search for protective environmental exposures in early life that could prevent subsequent asthma.

Asthma Pathogenesis: Epithelium and Eosinophils/T2 Responses as Culprits

The 1970s and 1980s demonstrated a surge of publications evaluating how structural changes of the airway in asthma lead to or modulate functional outcomes. Early seminal studies demonstrated that airway hyperresponsiveness is present in asthma, can be quantified, and modulates response to inhaled allergen, exercise, and asthma symptoms (17). The response of the airway to external irritants, including allergens, depends not only on cutaneous sensitivity to allergen but also on the degree of nonspecific airway hyperresponsiveness (18, 19). In the 1990s and into the 21st century, these observations led to the use of bronchoscopy and examination of autopsy specimens to better understand and describe the remarkable changes in airway structure that are known to occur in asthma. New findings of interest in the large and small airways included the presence of significant inflammation in the airway mucosa, particularly the eosinophils, lymphocytes, mast cells, and macrophages (20–29). Structural changes observed included smooth muscle hypertrophy and epithelial denudation (30, 31). A few investigations evaluated the effect of corticosteroid treatment on these airway changes, particularly the inflammatory component (32–34). The airway epithelium moved to center stage no longer as an innocent bystander but as an active participant in asthma pathobiology, especially regarding the exacerbation (35, 36).

These early, important observations led to the new concept of asthma heterogeneity in the inflammatory aspect of asthma that led to differences in clinical characteristics (phenotypes) and clinical outcomes (37, 38). It became clear that although the eosinophil is an important cell in the asthmatic airway, it certainly is not the dominant cell in all asthma, and some patients with asthma had very little inflammation at all (39). The field extended its reach by demonstrating that the neutrophil is a relevant cell in asthma (40), as are processes such as oxidative stress (41–44), corticosteroid resistance (45), and distal lung inflammation (46). Realizing that asthma was heterogeneous, the concept of collections of clinical characteristics or asthma phenotypes was born, as was further investigation into underlying mechanisms or endotypes driving these clinical phenotypes. What was first defined as eosinophilic and noneosinophilic asthma (37) is now subgrouped into several endotypes of asthma under the eosinophilic and noneosinophilic umbrellas, each driven by different groups of inflammatory mediators. Hence, the terms T-helper 2 or type 2 (Th2/T2) asthma are used to describe asthma driven by specific cytokines such as IL-4, -5, and -13, and non-Th2/type 2 asthma driven by cells such as the neutrophil (47) and other mediators such as IL-8, -17, -23 and transforming growth factor-β (48, 49). This terminology was introduced by Woodruff and colleagues (50) and others, on the shoulders of many investigators before them.

Asthma Treatment: Aiming at Precision Approaches

With the discovery that significant inflammatory as well as clinical heterogeneity is present in asthma, the stage was set for movement into the era of personalized or precision medicine. Biologics such as omalizumab showed promise (51), but not in every patient with asthma. Using cluster analysis to define clinical phenotypes, and hence endotypes (52), as well as biomarkers such as sputum and peripheral eosinophils (53), exhaled nitric oxide (43), and periostin (54), we are on the cusp of targeting the very specific biologic therapies available and under development to the correct patient. The controversy over the relevance of the eosinophil in asthma (39) in the 1990s demonstrates the lack of recognition of phenotypes/endotypes in asthma and also how far the field has moved forward.

Toward the Future

The Journal has published some of the most important milestones in asthma research in the last quarter century. It has historically provided the stage for major developments in our understanding of the origins, course, triggers, long-term outcome, pathogenesis, and treatment of this heterogeneous disease. The Journal aims at continuing to be a critical conduit for discoveries that will help defeat asthma, we hope in the near future.