The State of Asthma Research: Considerable Advances, but Still a Long Way to Go

We received many high-quality submissions for this Special Asthma edition of the Journal. The seven original manuscripts selected, to which we added concise clinical reviews in three global areas of clinical and translational interest, are a representative sample of the status of asthma research today. Our conclusion: there has been (some would say finally!) considerable progress in three major areas: deciphering the genetic roots of the disease, understanding the molecular basis of its heterogeneity, and using this new information to improve the lives of patients with the most severe forms of the disease. At the same time, major issues such as controlling exacerbations and attaining satisfactory adherence to inhaled therapy remain unresolved.

Genetics: A Bona Fide Asthma Locus

A decade after it was first reported by Moffatt and colleagues (1), it is due time to acknowledge that the identification of a cluster of polymorphisms in different genes associated with asthma in chromosome 17q21, the so-called ORMDL3 locus, is a major landmark in our understanding of the disease. The locus has been widely replicated in disparate populations (2) and found to be strongly associated with the first clinical manifestations of asthma in early life (3); that is, wheezing illnesses triggered by human rhinoviruses (HRV) (4). The connection among ORMDL3, HRV infection, and asthma remains unclear, but Zhang and colleagues (5) now offer a new, tantalizing insight: suppression of ORMDL3 in lung epithelial cells leads to reduction of IL-6 and IL-8 release after IL-1-β–induced inflammation, and decreases the expression of ICAM1, the main HRV adhesion site in the respiratory tract. Because the asthma-related ORMDL3 alleles are associated with increased expression of the gene (1), it is fair to speculate that risk alleles at the ORMDL3 locus may increase lower airway susceptibility to HRV in early life and, by this mechanism, predispose for subsequent asthma. Of great interest is the recent finding that microbial exposure could sharply decrease the incidence of wheezing illnesses in early life in carriers of the susceptibility alleles at the ORMDL3 locus (6). If confirmed, this finding opens exciting new avenues for asthma prevention in susceptible children.

Interestingly, Jia and colleagues (7) report diminished levels of ezrin in animal models of asthma and in exhaled breath condensate and serum of patients with asthma and airflow limitation. Ezrin is a protein expressed in epithelial cells that plays a critical role in cell–cell adhesion and cell morphology and polarity, and is involved in the activation of antiviral responses associated with ICAM1 engagement by HRV (8). Taken together with ORMDL3 studies by Zhang and colleagues (5), these results thus point squarely to inappropriate responses to viral infection as a potential major determinant of asthma risk in early life, and a precursor of severe disease later in life.

Disentangling Asthma Heterogeneity

Almost 80 years ago, Rackemann (9) first reviewed the evidence suggesting that there were at least two forms of asthma: extrinsic and intrinsic, or approximately T2-high and T2-low asthma if we use today’s nomenclature. There is no doubt that we have come a long way in our grasp of the molecular basis of T2-high asthma, but still, much more needs to be understood about it, and T2-low asthma remains essentially a mystery. Peters and colleagues (10) performed network transcriptomic analyses of sputum from patients with asthma and healthy control subjects, and identified a T2-ultra-high group of older patients with asthma with more severe airway obstruction. They also reported that T2-low patients showed a decrease in the expression of gene networks associated with CD8⁺ T cells, which in turn correlated inversely with both body mass index and circulating IL-6 levels. Unfortunately, in interpreting these results, we do not have the fixed anchoring point offered by a genetic locus consistently associated with asthma, as described earlier. It is thus not possible to know which networks and cells are responsible for disease pathogenesis and which are uninvolved bystanders engulfed in the inflammatory response. In the case in question, the potential role of IL-6 in T2-low asthma remains an intriguing (11) but still unproven possibility. Clinical trials using drugs that inhibit IL-6–mediated immune responses could offer a potentially definitive answer for this conundrum.

Biologics for T2-High Asthma: Identifying Responders and Characterizing Responses

A landmark advance in the treatment of severe asthma is the availability of a handful of powerful biologics that block different branches of the T2 response and have been convincingly shown to improve asthma control and prevent exacerbations in patients with severe disease (12). It is now clear that the availability of these new medicines has changed the treatment landscape and dramatically improved the lives of many of these patients. Still, these are all very expensive drugs, and identifying the patients that will or will not respond to their administration is a major challenge. For one of these drugs, reslizumab, a humanized monoclonal antibody against human IL-5, Bateman and colleagues (13) propose a mathematical algorithm that accurately identified those patients with severe asthma and eosinophilia who would show continued response to reslizumab after 1 year of use, based on changes in lung function, quality of life, and asthma control after 16 weeks of therapy. Unfortunately, the algorithm identified only a small number of nonresponders, and the predictive power for nonresponse was low (specificity of approximately 50%). It is thus likely that clinical outcomes will need to be combined with biomarkers to determine early during treatment who will, and particularly who will not, respond to new asthma therapies. The Precision Interventions for Severe and/or Exacerbation Prone Asthma (PrecISE) network funded by the NHLBI in the United States is currently applying such a combined strategy to test new, previously untried therapies for severe asthma (https://preciseasthma.org).

As effective as they are, biologics have complex effects on immune responses. To assess the influence of anti–IL-5 drugs on antiviral responses, Sabogal Piñeros and colleagues (14) experimentally infected with HRV-16 patients with mild asthma who had been treated with a single dose of mepolizumab (another anti–IL-5 biologic) or placebo 2 weeks earlier. Intriguingly, the researchers found that mepolizumab enhanced key components of the antiviral response (e.g., secretory IgA and circulating NK cells), but also reduced neutrophils and their activation and markedly affected RV16-induced MIP-3a, VEGF-A and IL-1RA. The result was significantly higher viral load in nasal swabs. Whether these effects are exclusive of mild asthma, and whether they have a role in determining asthma control, is not known, but clearly more needs to be understood about the way in which biologics may interfere with antiviral immune responses.

Exacerbations and Adherence to Inhaled Therapy: The Continued Challenge

In spite of the undeniable progress made in the last decade, major challenges remain. Asthma exacerbations continue to cause hundreds of thousands of hospitalizations in the United States each year (15). They more often strike disadvantaged populations (16), and affect patients with severe disease in particular, but most patients who develop exacerbations do not have severe asthma, and it is very difficult to predict which patients will be affected (17). There is one factor, however, that if addressed, could significantly decrease exacerbations: improved adherence to inhaled corticosteroids, with or without long-acting β-agonists. Unfortunately, we are not winning that battle: adherence is still much lower than it should be to ensure effectiveness (18). Moreover, many patients for whom expensive biologics are prescribed were not adherent to inhaled therapy during the previous year (19). The study by Heaney and coworkers (20) suggests that monitoring fraction of exhaled nitric oxide suppression, adherence to inhaled therapy, and blood eosinophil count could identify patients who will or will not respond to such therapy, and thus better select those to be treated with biologics. Unfortunately, the devices used to assess suppression of fraction of exhaled nitric oxide are expensive, and not all patients were able to follow the procedures involved in the complex study design. Technology may eventually help to improve adherence, but at this time, there is no alternative to establishing a therapeutic partnership between practitioners and patients in which the needs, expectations, and obstacles patients face are included in the clinical decision-making process (21).