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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: Lachowicz-Scroggins ME, Dunican EM, Charbit AR, Raymond W, Looney MR, Peters MC, Gordon ED, Woodruff PG, Lefrançais E, Phillips BR, Mauger DT, Comhair SA, Erzurum SC, Johansson MW, Jarjour NN, Coverstone AM, Castro M, Hastie AT, Bleecker ER, Fajt ML, Wenzel SE, Israel E, Levy BD, Fahy JV. Extracellular DNA, Neutrophil Extracellular Traps, and Inflammasome Activation in Severe Asthma. Am J Respir Crit Care Med. 2019 May 1;199(9):1076-1085. doi: 10.1164/rccm.201810-1869OC. PubMed PMID: 30888839.

2: Schaefer N, Li X, Seibold MA, Jarjour NN, Denlinger LC, Castro M, Coverstone AM, Teague WG, Boomer J, Bleecker ER, Meyers DA, Moore WC, Hawkins GA, Fahy J, Phillips BR, Mauger DT, Dakhama A, Gellatly S, Pavelka N, Berman R, Di YP, Wenzel SE, Chu HW. The effect of BPIFA1/SPLUNC1 genetic variation on its expression and function in asthmatic airway epithelium. JCI Insight. 2019 Apr 18;4(8). pii: 127237. doi: 10.1172/jci.insight.127237. eCollection 2019 Apr 18. PubMED PMID: 30996135.

3: Wu W, Bang S, Bleecker ER, Castro M, Denlinger L, Erzurum SC, Fahy JV, Fitzpatrick AM, Gaston BM, Hastie AT, Israel E, Jarjour NN, Levy BD, Mauger DT, Meyers DA, Moore WC, Peters M, Phillips BR, Phipatanakul W, Sorkness RL, Wenzel SE. Multiview Cluster Analysis Identifies Variable Corticosteroid Response Phenotypes in Severe Asthma. Am J Respir Crit Care Med. 2019 Jan 25. doi: 10.1164/rccm.201808-1543OC. PubMed PMID: 30682261.


Lay Summary: Despite the importance of corticosteroids (CSs) for asthma management, CSs are also known for their numerous harmful side effects and range of responses among patients with asthma. To better understand the CS responsive patterns, we utilized machine learning to characterize differential CS responses among subjects with asthma. We partitioned 346 adult participants with asthma in the Severe Asthma Research Program with paired (before and 2–3 weeks after triamcinolone administration) data, based on 100 clinical, physiological, inflammatory, and demographic variables.
Four clusters of individuals with asthma and different CS responses were identified. Clusters 1 and 2 consisted of young patients with allergic asthma and relatively normal lung function who were modestly responsive to CSs.  Patients in cluster 3 developed asthma later in life and had low lung function, high baseline eosinophils, and the greatest CS responsiveness. Cluster 4 patients were primarily of young, obese women with severe airway obstruction, little eosinophilic inflammation, and poor response to CS.   Twelve selective baseline variables were then identified that accurately predicted the patient’s cluster assignment (and response to CSs). In summary, machine learning can provide    new insights the factors which influence CS responsiveness and could ultimately lead to improved asthma management.


4: Fitzpatrick AM, Gillespie SE, Mauger DT, Phillips BR, Bleecker ER, Israel E, Meyers DA, Moore WC, Sorkness RL, Wenzel SE, Bacharier LB, Castro M, Denlinger LC, Erzurum SC, Fahy JV, Gaston BM, Jarjour NN, Larkin A, Levy BD, Ly NP, Ortega VE, Peters SP, Phipatanakul W, Ramratnam S, Teague WG. Racial disparities in asthma-related health care use in the National Heart, Lung, and Blood Institute's Severe Asthma Research Program. J Allergy Clin Immunol. 2019 Jan 8. pii: S0091-6749(18)31732-9. doi: 10.1016/j.jaci.2018.11.022. PubMed PMID: 30635198.


Lay Summary: National asthma surveillance data highlight disturbing trends in asthma disparities. Self-reported black patients have a higher prevalence of current asthma and substantially greater asthma morbidity than other racial groups.
Lay Summary: In a research article recently published in The Journal of Allergy and Clinical Immunology (JACI), Fitzpatrick and colleagues in the National Heart, Lung and Blood Institute’s (NHLBI) Severe Asthma Research Program (SARP) assessed differenced in healthcare utilization between self-reported Black and White patients with asthma. The study included 579 participants 6 years and older, each observed for one year. Data were analyzed according to a conceptual framework after application of statistical propensity scoring methods to balance the patient groups for other factors associated with healthcare usage.
Self-reported Black patients with asthma were more than twice as likely to visit the emergency department (ED) for asthma over one year. However, when the statistics were weighted and balanced based on socioeconomic factors and environmental exposures, the racial differences evened out. Furthermore, after statistical weighting, self-reported Black patients with asthma were 43 percent less likely to see a physician or healthcare provider in an outpatient setting for asthma care.
These results highlight the complex nature of asthma disparities and highlight the need for social and environmental policies and interventions to reduce asthma disparities in self-reported Black populations. Further examination of healthcare access, mistrust with the medical system, differences in the lived asthma experience including symptom perception are also needed.


5: Krishnamoorthy N, Douda DN, Brüggemann TR, Ricklefs I, Duvall MG, Abdulnour
RE, Martinod K, Tavares L, Wang X, Cernadas M, Israel E, Mauger DT, Bleecker ER, 
Castro M, Erzurum SC, Gaston BM, Jarjour NN, Wenzel S, Dunican E, Fahy JV, Irimia
D, Wagner DD, Levy BD; National Heart, Lung, and Blood Institute Severe Asthma
Research Program-3 Investigators. Neutrophil cytoplasts induce T(H)17
differentiation and skew inflammation toward neutrophilia in severe asthma. Sci
Immunol. 2018 Aug 3;3(26). pii: eaao4747. doi: 10.1126/sciimmunol.aao4747. PubMed
PMID: 30076281.

6: Ash SY, Rahaghi FN, Come CE, Ross JC, Colon AG, Cardet-Guisasola JC, Dunican
EM, Bleecker ER, Castro M, Fahy JV, Fain SB, Gaston BM, Hoffman EA, Jarjour NN,
Mauger DT, Wenzel SE, Levy BD, San Jose Estepar R, Israel E, Washko GR; SARP
Investigators. Pruning of the Pulmonary Vasculature in Asthma: The SARP Cohort.
Am J Respir Crit Care Med. 2018 Apr 19. doi: 10.1164/rccm.201712-2426OC. [Epub
ahead of print] PubMed PMID: 29672122.

7: DeBoer MD, Phillips BR, Mauger DT, Zein J, Erzurum SC, Fitzpatrick AM, Gaston 
BM, Myers R, Ross KR, Chmiel J, Lee MJ, Fahy JV, Peters M, Ly NP, Wenzel SE, Fajt
ML, Holguin F, Moore WC, Peters SP, Meyers D, Bleecker ER, Castro M, Coverstone
AM, Bacharier LB, Jarjour NN, Sorkness RL, Ramratnam S, Irani AM, Israel E, Levy 
B, Phipatanakul W, Gaffin JM, Gerald Teague W. Effects of endogenous sex hormones
on lung function and symptom control in adolescents with asthma. BMC Pulm Med.
2018 Apr 10;18(1):58. doi: 10.1186/s12890-018-0612-x. PubMed PMID: 29631584;
PubMed Central PMCID: PMC5891903.

8: Peters MC, Kerr S, Dunican EM, Woodruff PG, Fajt ML, Levy BD, Israel E,
Phillips BR, Mauger DT, Comhair SA, Erzurum SC, Johansson MW, Jarjour NN,
Coverstone AM, Castro M, Hastie AT, Bleecker ER, Wenzel SE, Fahy JV; 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. [Epub ahead of print] PubMed PMID: 29524537.


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 

9: Choi S, Haghighi B, Choi J, Hoffman EA, Comellas AP, Newell JD, Wenzel SE,
Castro M, Fain SB, Jarjour NN, Schiebler ML, Barr RG, Han MK, Bleecker ER, Cooper
CB, Couper D, Hansel N, Kanner RE, Kazeroni EA, Kleerup EAC, Martinez FJ, O'Neal 
WK, Woodruff PG, Lin CL. Differentiation of quantitative CT imaging phenotypes in
asthma versus COPD. BMJ Open Respir Res. 2017 Nov 9;4(1):e000252. doi:
10.1136/bmjresp-2017-000252. eCollection 2017. Erratum in: BMJ Open Respir Res.
2018 Mar 6;5(1):e000252corr1. PubMed PMID: 29435345; PubMed Central PMCID:
PMC5687530.

10: Shim SS, Schiebler ML, Evans MD, Jarjour N, Sorkness RL, Denlinger L,
Rodriguez A, Wenzel S, Hoffman EA, Lin CL, Gierada DS, Castro M, Fain SB; 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.

11: Dunican EM, Elicker BM, Gierada DS, Nagle SK, Schiebler ML, Newell JD, Raymond
WW, Lachowicz-Scroggins ME, Di Maio S, Hoffman EA, Castro M, Fain SB, Jarjour NN,
Israel E, Levy BD, Erzurum SC, Wenzel SE, Meyers DA, Bleecker ER, Phillips BR,
Mauger DT, Gordon ED, Woodruff PG, Peters MC, Fahy JV; National Heart Lung and
Blood Institute (NHLBI) Severe Asthma Research Program (SARP). Mucus plugs in
patients with asthma linked to eosinophilia and airflow obstruction. J Clin
Invest. 2018 Feb 5. pii: 95693. doi: 10.1172/JCI95693. [Epub ahead of print]
PubMed PMID: 29400693.

12: Georas SN. All plugged up - noninvasive mucus score to assess airway
dysfunction in asthma. J Clin Invest. 2018 Feb 5. pii: 99726. doi:
10.1172/JCI99726. [Epub ahead of print] PubMed PMID: 29400694.

13: Wong-McGrath K, Denlinger LC, Bleecker ER, Castro M, Gaston B, Israel E,
Jarjour NN, Mauger DT, Peters S, Phillips BR, Wenzel SE, Fahy JV, Peters MC;
National Heart Lung and Blood Institute’s Severe Asthma Research Program-3
Investigators. Internet-Based Monitoring in the Severe Asthma Research Program
Identifies a Subgroup of Patients With Labile Asthma Control. Chest. 2017 Oct 26.
pii: S0012-3692(17)32919-7. doi: 10.1016/j.chest.2017.10.017. [Epub ahead of
print] PubMed PMID: 29080709.

Lay Summary: Internet-Based Monitoring Systems (IBS) have the potential to improve understanding of disease behavior, especially in chronic diseases like asthma. In this study we evaluated the usefulness of internet based monitoring as a research tool for monitoring asthma control is patients enrolled in the Severe Asthma Research Program. We found that subject participation with the internet based monitoring tool was influenced by race, socioeconomic status, and asthma control. Among that patients that participated with internet based monitoring we identified a sub-group of asthma patients with asthma symptoms that fluctuated significantly throughout the study. These patients with labile asthma control were characterized by an increased susceptibility to cold and flulike illness and a high body mass index.
Conclusion:
- Participation in internet-based monitoring in asthma is influenced by race, socioeconomic status, and asthma control
- Asthma patients with labile asthma control are characterized by an increased susceptibility to develop colds and flulike illness and high rates of obesity.

14: Duvall MG, Barnig C, Cernadas M, Ricklefs I, Krishnamoorthy N, Grossman NL, Bhakta NR, Fahy JV, Bleecker ER, Castro M, Erzurum SC, Gaston BM, Jarjour NN, Mauger DT, Wenzel SE, Comhair SA, Coverstone AM, Fajt ML, Hastie AT, Johansson MW, Peters MC, Phillips BR, Israel E, Levy BD; National Heart, Lung, and Blood Institute’s Severe Asthma Research Program-3 Investigators. Natural Killer Cell-Mediated Inflammation Resolution Is Disabled In Severe Asthma. Sci Immunol. 2017 Mar 10;2(9). pii: eaam5446. doi: 10.1126/sciimmunol.aam5446. PubMed PMID: 28783702.

Lay Summary: 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.

15: Ricklefs I, Barkas I, Duvall MG, Cernadas M, Grossman NL, Israel E, Bleecker
ER, Castro M, Erzurum SC, Fahy JV, Gaston BM, Denlinger LC, Mauger DT, Wenzel SE,
Comhair SA, Coverstone AM, Fajt ML, Hastie AT, Johansson MW, Peters MC, Phillips 
BR, Levy BD; 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.

16:  Teague WG, Phillips BR, Fahy JV, Wenzel SE, Fitzpatrick AM, Moore WC, Hastie AT, Bleecker ER, Meyers DA, Peters SP, Castro M, Coverstone AM, Bacharier LB, Ly NP, Peters MC, Denlinger LC, Ramratnam S, Sorkness RL, Gaston BM, Erzurum SC, Comhair SAA, Myers RE, Zein J, DeBoer MD, Irani A-M, Israel E, Levy B, Cardet JC, Phipatanakul W, Gaffin JM, Holguin F, Fajt ML, Aujla SJ, Mauger DT, Jarjour NN, 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


Lay summary: 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.  


17: Denlinger LC, Phillips BR, Ramratnam S, Ross K, Bhakta NR, Cardet JC, Castro
M, Peters SP, Phipatanakul W, Aujla S, Bacharier LB, Bleecker ER, Comhair SA,
Coverstone A, DeBoer M, Erzurum SC, Fain SB, Fajt M, Fitzpatrick AM, Gaffin J,
Gaston B, Hastie AT, Hawkins GA, Holguin F, Irani AM, Israel E, Levy BD, Ly N,
Meyers DA, Moore WC, Myers R, Opina MT, Peters MC, Schiebler ML, Sorkness RL,
Teague WG, Wenzel SE, Woodruff PG, Mauger DT, Fahy JV, Jarjour NN; National
Heart, Lung, and Blood Institute’s Severe Asthma Research Program-3
Investigators. 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.


Lay Summary:  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.

18: Choi S, Hoffman EA, Wenzel SE, Castro M, Fain S, Jarjour N, Schiebler ML, Chen
K, Lin CL; National Heart, Lung and Blood Institute’s Severe Asthma Research
Program. 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. [Epub ahead of print] PubMed PMID: 28143694.


Lay Summary:  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.


19: Phipatanakul W, Mauger DT, Sorkness RL, Gaffin JM, Holguin F, Woodruff PG, Ly 
NP, Bacharier LB, Bhakta NR, Moore WC, Bleecker ER, Hastie AT, Meyers DA, Castro 
M, Fahy J, Fitzpatrick A, Gaston BM, Jarjour NN, Levy BD, Peters SP, Teague WG,
Fajt M, Wenzel SE, Erzurum SC, Israel E; and the Severe Asthma Research Program..
Effects of Age and Disease Severity on Systemic Corticosteroid Responses in
Asthma. Am J Respir Crit Care Med. 2016 Dec 14. [Epub ahead of print] PubMed
PMID: 27967215.


Lay Summary:  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. 

20: Luyster FS, Strollo PJ Jr, Holguin F, Castro M, Dunican EM, Fahy J, Gaston B, 
Israel E, Jarjour NN, Mauger DT, Moore WC, Wenzel SE. Association Between
Insomnia and Asthma Burden in the Severe Asthma Research Program (SARP) III.
Chest. 2016 Dec;150(6):1242-1250. doi: 10.1016/j.chest.2016.09.020. PubMed PMID: 
27720882.


Lay Summary:  Our study found over a third of adults with asthma have insomnia. Those with insomnia had more depression and anxiety, poorer quality of life, and had more frequent asthma-related health care use in the past year than those without insomnia. Patients with asthma should be evaluated for insomnia and provided insomnia treatment if needed by their healthcare provider.

Insomnia is an inability to get a good night’s sleep on a regular basis . It was found in 37% of adults with asthma. Those with insomnia had more symptoms of depression and anxiety and worse quality of life than those without insomnia. Also, patients who reported insomnia had more frequent doctor visits, emergency room visits, and hospitalizations because of their asthma than those without insomnia. These findings suggest patients with asthma should be asked about sleep problems and provided treatment for insomnia if needed by their doctor.

21: Peters MC, McGrath KW, Hawkins GA, Hastie AT, Levy BD, Israel E, Phillips BR, 
Mauger DT, Comhair SA, Erzurum SC, Johansson MW, Jarjour NN, Coverstone AM,
Castro M, Holguin F, Wenzel SE, Woodruff PG, Bleecker ER, Fahy JV; National
Heart, Lung, and Blood Institute Severe Asthma Research Program. Plasma
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.


Lay Summary: 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.


22: Altes TA, Mugler JP 3rd, Ruppert K, Tustison NJ, Gersbach J, Szentpetery S,
Meyer CH, de Lange EE, Teague WG. 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.


Lay Summary:  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.