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


Key Recent SARP III Publications

                                               

1.     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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2.     Teague WG, et al.Baseline Features of the Severe Asthma Research Program (SARP III) Cohort: Differences with Age, The Journal of Allergy and Clinical Immunology: In Practice, doi:10.1016/j.jaip.2017.05.032 PubMed PMID: 28866107. 

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.  
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3.     Denlinger LC, et al. Inflammatory and Comorbid Features of Patients with Severe Asthma and Frequent Exacerbations. Am J Respir Crit Care Med. 2017 Feb 1;195(3):302-313. doi: 10.1164/rccm.201602-0419OC. PubMed PMID: 27556234. 

This is a multicenter cohort study of adults and children with severe asthma. Blood eosinophils, bronchodilator responsiveness, body mass index, chronic sinusitis, and gastroesophageal reflux disease were found to be associated with exacerbation-prone asthma, after adjustment for age, sex, race, center, and medication adherence, with replication of these findings in a second cohort. Exacerbation-prone asthma is a distinct phenotype with prominent extrapulmonary features that may be modifiable.

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4.     Choi S, et al. Quantitative computed tomography imaging-based clustering differentiates asthmatic subgroups with distinctive clinical phenotypes. J Allergy Clin Immunol. 2017 Jan 28. pii: S0091-6749(17)30146-X. doi: 10.1016/j.jaci.2016.11.053. PubMed PMID: 28143694.

The unique structural and functional alterations observed in each imaging cluster provide a basis for new insights for the existing pathophysiology of asthma. The clustering membership can be used for a basis for the development of effective interventions for asthmatics in the future. 

Severe asthma can be quite different from patient to patient – a new approach to “cluster” these patients into groups to understand their disease better has been done. The SARP imaging cluster study added CT scans of the chest to the information we gathered on our patients. We found unique changes in the windpipes and lungs of the patients in these clusters. Our hope is this information can be used to target treatment better in the future. 

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5.     Phipatanakul W, et al. Effects of Age and Disease Severity on Systemic Corticosteroid Responses in Asthma. Am J Respir Crit Care Med. 2017 Jun 1;195(11):1439-1448. doi: 10.1164/rccm.201607-1453OC. PMID: 27967215 

Adults, but not children remain different after a corticosteroid injection, suggesting that children may have more responsive disease. Regardless, 20% of children and adults with severe asthma, despite already being on high dose inhaled corticosteroids have a clinically important improvement in lung function. These findings suggest differences between children and adults with severe asthma and that following these patients over time will be important to furthering our understanding of the disease and its response to therapies.

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6.    Altes TA, et al. Clinical correlates of lung ventilation defects in asthmatic children. J Allergy Clin Immunol. 2016 Mar;137(3):789-96.e7. doi: 10.1016/j.jaci.2015.08.045. PubMed PMID: 26521043. 

This study showed that a new method using inhaled hyperpolarized helium-3 gas can be safely used to image by MRI the pattern of ventilation in the lungs of children with asthma. This method has significant advantages over standard chest CT in that there is no exposure to ionizing radiation. We learned that children with severe asthma have greater regions of the lung which do not get enough air, and that the volume of these poorly ventilated regions correlates significantly with many of the features of asthma.

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7.    Duvall MG, et al. Natural 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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8     Shim SS, et al.  NHLBI Severe Asthma Research Program. Lumen area change (Delta Lumen) between inspiratory and expiratory CT as a measure of severe outcomes in asthma. J Allergy Clin Immunol. 2018 Feb 10. pii: S0091-6749(18)30219-7. doi: 10.1016/j.jaci.2017.12.1004. [Epub ahead of print] PubMed PMID: 29438772.