Asthma and lower airway disease

The other side of asthma: Steroid-refractory disease in the absence of T_H2-mediated inflammation

To examine the roots of asthma across different ages, including atopy, the role of the microbiome and viral infections, and comorbidities and confounders, such as obesity, aspirin-exacerbated respiratory disease, neutrophilic asthma, cigarette smoking, and the possibility of an asthma–chronic obstructive pulmonary disease overlap syndrome.

Data were taken from various scientific search engines, including PubMed and Science Direct databases.

Articles that reviewed information on the origins of asthma in persons of all ages, including different phenotypes and genotypes of asthma, were used.

Asthma is a common and complex disease whose origins are likely a combination of both genetic predisposition and environmental exposures. Factors such as the microbiome, other atopic disease, viral infections in young children, and other diagnoses, such as obesity or aspirin-exacerbated respiratory disease, are important to consider when creating a treatment plan for patients.

Asthma is a disease that is often diagnosed in childhood but can present at any age. There is debate in the field as to whether asthma is one disease or several different diseases that include airway inflammation as a key finding. There are risk factors for disease in the environment and through comorbidities that likely play significant roles in the origins of asthma, the development of symptoms, and the response to treatment. These factors are even more important as we look toward the future with the goal of personalized medicine.

Paradoxically, the vast majority of research models intended to understand the relationship between exogenous exposures and lung disease are reduced to a single inhalant. This approach is understandable given the practical challenges of investigation, but it is problematic in terms of translation to the real-world human condition. Furthermore, use of data from such models can lead to underestimation of effect, which may adversely influence regulatory imperatives to protect public health based on the most robust information. Efforts to incrementally introduce layers of complexity to observational and experimental systems have revealed pathophysiology previously “hidden” within simplified models. Capturing the effects of co-exposure to traffic-related air pollution and allergens is a paradigmatic example and illustrates the influence of co-exposures across a plethora of clinical and subclinical end points within the respiratory tract. From DNA methylation in the epithelium, to inflammatory mediators and allergen-specific antibodies in the airway, to airflow limitation and symptoms, the addition of a common second exposure induces profound changes. In addition, genetic variation significantly alters the product of these relationships, and capturing multidimensional interactions may reveal susceptible populations who are particularly affected by these exposures and may merit focused measures for protection. Collectively, better modeling, and ultimately deeper knowledge, of these complex relationships has important implications for personalized health and prevention, development and refinement of pharmacologic agents, and public health responses to climate change and the staggering burden of pollution-driven disease worldwide.

For several decades, the leukotriene pathways have been implicated as playing a central role in the pathophysiology of asthma. The presence and elevation of numerous metabolites in the blood, sputum, and bronchoalveolar lavage fluid from asthmatics or experimental animals adds support to this notion. However, targeting of the leukotriene pathways has had, in general, limited success. The single exception in asthma therapy has been targeting of the cysteinyl leukotriene receptor 1, which clinically has proven effective but only in certain clinical situations. Interference with 5-lipoxygenase has had limited success, in part due to adverse drug effects. The importance of the LTB4-BLT1 pathway in asthma pathogenesis has extensive experimental support and findings, albeit limited, from clinical samples. The LTB4-BLT1 pathway was shown to be important as a neutrophil chemoattractant. Despite observations made more than two decades ago, the LTB4-BLT1 pathway has only recently been shown to exhibit important activities on subsets of T lymphocytes, both as a chemoattractant and on lymphocyte activation, as well as on dendritic cells, the major antigen presenting cell in the lung. The role of BLT2 in asthma remains unclear. Targeting of components of the LTB4-BLT1 pathway offers innovative therapeutic opportunities especially in patients with asthma that remain uncontrolled despite intensive corticosteroid treatment.

Despite progress in the diagnosis and management of asthma, many patients have poorly controlled or refractory asthma (RA). The mechanism of this RA is not well understood.

We sought to explore the relationship between neutrophils and other biomarkers of RA.

Sixty patients with RA, 30 patients with nonrefractory asthma (NRA), and 20 healthy subjects were enrolled. We performed a comprehensive characterization of these study subjects, which included laboratory and pulmonary function studies, chest computed tomography, and bronchoscopy with bronchoalveolar lavage (BAL). We analyzed BAL fluid and serum for a total of 244 biomolecules using a multiplex assay and correlated them with clinical and other laboratory parameters.

RA was significantly different from NRA with regard to pulmonary function indices, bronchial basement membrane thickness, and BAL fluid neutrophil and lymphocyte counts but not eosinophil counts. BAL fluid neutrophil counts negatively and positively correlated with forced vital capacity and age, respectively. Of the 244 biomolecules studied, 52 and 14 biomolecules from BAL fluid and serum, respectively, were significantly different among the study groups. Thirteen of these 52 molecules correlated with BAL fluid neutrophil counts. BAL fluid from 40% of patients with RA was positive for a pathogenic microbe. Infection-negative neutrophilic RA was associated with an increase in levels of select biomarkers of inflammation in the serum, suggesting the presence of systemic inflammation.

RA was associated with increased numbers of neutrophils and proneutrophilic biomolecules in the airways. Subclinical infection was present in 40% of patients with RA, which likely contributed to neutrophilic inflammation. A subgroup of patients with noninfected neutrophilic RA was associated with systemic inflammation.

The mechanism of T_H2/T_H17-predominant and T_H2/T_H17-low asthma is unknown.

We sought to study the immune mechanism of T_H2/T_H17-predominant and T_H2/T_H17-low asthma.

In a previously reported cohort of 60 asthmatic patients, 16 patients were immunophenotyped with T_H2/T_H17-predominant asthma and 22 patients with T_H2/T_H17-low asthma. We examined bronchoalveolar lavage (BAL) fluid leukocytes, cytokines, mediators, and epithelial cell function for these asthma subgroups.

Patients with T_H2/T_H17-predominant asthma had increased IL-1β, IL-6, IL-23, C3a, and serum amyloid A levels in BAL fluid, and these correlated with IL-1β and C3a levels. T_H2/T_H17 cells expressed higher levels of the IL-1 receptor and phospho-p38 mitogen-activated protein kinase. Anakinra, an IL-1 receptor antagonist protein, inhibited BAL T_H2/T_H17 cell counts. T_H2/T_H17-low asthma had 2 distinct subgroups: neutrophilic asthma (45%) and pauci-inflammatory asthma (55%). This contrasted with patients with T_H2/T_H17-predominant and T_H2-predominant asthma, which included neutrophilic asthma in 6% and 0% of patients, respectively. BAL fluid neutrophils strongly correlated with BAL fluid myeloperoxidase, IL-8, IL-1α, IL-6, granulocyte colony-stimulating factor, and GM-CSF levels. Sixty percent of the patients with neutrophilic asthma had a pathogenic microorganism in BAL culture, which suggested a subclinical infection.

We uncovered a critical role for the IL-1β pathway in patients with T_H2/T_H17-predminant asthma. A subgroup of patients with T_H2/T_H17-low asthma had neutrophilic asthma and increased BAL fluid IL-1α, IL-6, IL-8, granulocyte colony-stimulating factor, and GM-CSF levels. IL-1α was directly involved in IL-8 production and likely contributed to neutrophilic asthma. Sixty percent of neutrophilic patients had a subclinical infection.