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Severe Asthma Research Program
A National Institutes of Health/ National Heart, Lung & Blood Institute sponsored network


Molecular Phenotypes

1.    Peters MC, et alPlasma interleukin-6 concentrations, metabolic dysfunction, and asthma severity: a cross-sectional analysis of two cohorts. Lancet Respir Med. 2016 Jul;4(7):574-84. doi: 10.1016/S2213-2600(16)30048-0. PubMed PMID: 27283230; PubMed Central PMCID: PMC5007068. 

Severe asthma is a complex disease frequently associated with older age and obesity. Low grade systemic inflammation often occurs in obesity and is associated with insulin resistance, atherosclerosis, type-2 diabetes and hypertension. However, the role of systemic inflammation and metabolic dysfunction as a risk factor for having severe asthma is poorly understood. In this study, we measured blood levels of interleukin-6 (IL-6) a protein commonly increased in patients with obesity. We found that increased blood IL6 levels were strongly associated with severe asthma and that subjects with high IL6 levels had other markers of metabolic dysfunction, including higher rates of hypertension and diabetes. This work suggests that obesity and IL6 related systemic inflammation could be a unique mechanism in severe asthma and that inflammation originating outside the lung can play a critical role in triggering disease pathology inside the lung.

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​2.     Peters MC, et al. National Heart Lung and Blood Institute Severe Asthma Research Program-3. Refractory Airway Type-2 Inflammation in a Large Subgroup of Asthmatics treated with Inhaled Corticosteroids. J Allergy Clin Immunol. 2018 Mar 7. pii: S0091-6749(18)30390-7.  doi: 10.1016/j.jaci.2017.12.1009. PubMed PMID: 29524537.

The goal of this project was to examine the baseline features of children and adults with severe and non-severe asthma enrolled in the SARP long-term study.  We thought it would be interesting to see how these features are different with age and whether or not there was an interaction between age and asthma severity in regards to any one feature.  We discovered that severe asthma in children is highly associated with inflammatory factors like allergy, blood eosinophils, and expired nitric oxide, but the degree of allergic sensitization was not different in children with severe compared to non-severe asthma.  At entry into the SARP program, adults with asthma had overall lower inflammatory factors compared to children, but with age those factors were relatively higher in adults with severe compared to non-severe asthma.  What was most different in adults compared to children with severe asthma was the amount of airflow limitation, and less improvement in air flow following inhaled albuterol, a bronchodilator which relaxes the muscle tone in the airways.  The most important result of the paper was that at entry into the SARP Study, children with severe asthma had relatively more allergy-related inflammation but normal lung function, whereas adults with severe asthma had more complex patterns of inflammation with reduced lung function.

Lay Summary: 

Allergic inflammation, or type-2 inflammation, is increased in people with asthma but is typically improved with corticosteroid treatment. However, a group of people with severe asthma has persistent asthma symptoms despite treatment with inhaled corticosteroids. In this paper we used specialized techniques to measured allergic inflammation in sputum samples from subjects in the severe asthma research program who were taking inhaled corticosteroids. We found that a large group of severe asthma patients have increased airway allergic inflammation despite treatment with inhaled corticosteroids, and these allergic inflammation measurements remained high even after a corticosteroid injection. Furthermore, we found that these patients tended to be older in age and have more severe asthma. Finally, we also assessed whether we could use blood test measurements to predict whether a person would have airway allergic inflammation that was resistant to corticosteroids.

Conclusion:

-Inhaled or systemic corticosteroids do not fully suppress airway measures of allergic inflammation in a large sub-group of severe asthma patients.

- Patients with steroid resistant allergic inflammation asthma are usually older with more severe disease.

- Increased body weight and age modify the performance of blood-based biomarkers of airway allergic inflammation

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3.    Duvall MG, et alNatural Killer Cell-Mediated Inflammation Resolution Is Disabled In Severe Asthma. Sci. Immunol. 2, eaam5446 (2017) doi: 10.1126/sciimmunol.aam5446 

Anti-inflammatory corticosteroids are a first line of defense against many types of asthma, but patients with severe asthma do not frequently respond to this therapy. We determined that this lack of response may be due in part to defects in natural killer (NK) cells, which are important mediators of inflammation resolution. We found that NK cells from patients with severe asthma had impaired killing and that corticosteroid exposure further inhibited the function of these cells, whereas the proresolving mediator LXA4 preserved NK cell effector mechanisms. Therefore, corticosteroids may be a counterproductive therapy in patients with severe asthma, and specifically activating NK cells may provide an alternate therapeutic target.

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4.    Ricklefs I, et al.  National Heart Lung and Blood Institute’s Severe Asthma Research Program-3 Investigators. ALX receptor ligands define a biochemical endotype for severe asthma. JCI Insight. 2017 Jul 20;2(14). pii: 93534. doi: 10.1172/jci.insight.93534. [Epub ahead of print] PubMed PMID: 28724795; PubMed Central PMCID: PMC5518567.

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 5.    (Boston – Baumann) Neutrophil Predominant Lung Inflammation in Severe Asthma is Associated with Increased Serum Amyloid A and Decreased Lipoxin A4. Accepted to JCI.