- Email: [email protected]
Neutrophilic asthma: a distinct target for treatment?
Comment
Over the past decade, eosinophilic asthma, which is characterised by raised circulating eosinophil counts, has become an established phenotype. These patients are at risk of exacerbations but respond to corticosteroid therapy. Furthermore, biological therapies targeted at interleukin 5, a T-helper-2 cytokine important in the terminal differentiation and activation of eosinophils, have been effective in patients with severe and recurrent exacerbations, which further supports eosinophilic asthma as a distinct phenotype.1 By contrast, the neutrophilic non-eosinophilic asthma phenotype remains less-well defined although 50% of patients with symptomatic asthma are thought to have it. This phenotype is described as high neutrophil counts in sputum ranging from 40% to 76% of sputum cells. Increased neutrophil counts in sputum have been associated with severe asthma, corticosteroid insensitivity, and chronic airflow obstruction,2–4 and are seen during acute exacerbations.5 These associations have led to the notion that neutrophil infiltration into the airways might have a crucial role in the pathophysiological processes underlying severe asthma. Another possibility, however, is that increased numbers of neutrophils in the airways could be the result of infection, exposure to air pollutants, or treatment with corticosteroids—particularly oral corticosteroids, which are used on a daily basis by more than 40% of patients with severe asthma—and might merely be innocent bystanders. Various neutrophilic chemokines have been implicated in neutrophil recruitment in patients with severe neutrophilic asthma, including GROα, interleukin 8, CXCL10, and CCL2, with patients having raised concentrations of these chemokines in sputum.2,6 It is in this context that Paul O’Byrne and colleagues,7 in The Lancet Respiratory Medicine, explore the role for a CXCR2 antagonist in the treatment of patients with uncontrolled persistent asthma. AZD5069 is a CXCR2 chemokine receptor antagonist that blocks the effects of interleukin 8. The researchers did a 6-month phase 2b study in 640 patients with uncontrolled persistent asthma who were taking a combination of high-dose inhaled corticosteroids and long-acting β₂ agonists. Neutrophilic asthma was defined as eosinophil counts in blood lower than 0·5 × 10⁹/L, IgE concentrations in
serum lower than 750 kIU/L, and neutrophil counts in blood greater than 2·7 × 10⁹/L. Patients were randomly assigned to receive 5, 15, or 45 mg oral AZD5069 twice daily or matched placebo as add-on therapy to standard treatment. Although, as expected, AZD5069 reduced mean blood neutrophil counts, by up to 20·5% after 6 months of treatment with the 45 mg dose, no difference was seen compared with placebo in the rate of severe exacerbations, asthma symptoms, or lung function. These negative results follow on from those seen in studies of inhibitors of the neutrophilic pathway in patients with moderate to severe asthma, including golimumab, an antibody against TNFα,8 brodalumab, an antibody against interleukin 17 receptor,9 and the macrolide antibiotic, azithromycin.10 Those studies were not stratified by inflammatory phenotype; however, the importance of stratification was illustrated in the azithromycin study, in which a predefined subgroup with non-eosinophilic severe asthma (eosinophil counts in blood <0·2×10⁹/L) showed reductions in the rates of severe exacerbations and lower respiratory tract infections with azithromycin treatment, whereas there was no effect when the non-stratified group was analysed as a whole.10 In the study of O’Byrne and colleagues,7 although the neutrophilic asthma phenotype was based on the presence of high blood neutrophil counts, the eosinophil count cutoff was high (0·5×10⁹/L) and, therefore, some patients with eosinophilic asthma might have been included. Additionally, neutrophil counts in blood and sputum are weakly correlated and poorly predictive of sputum neutrophilia,11 which suggests that blood neutrophil count might not be a good marker of neutrophilic asthma. As noted by O’Byrne and colleagues,7 though, the measurement of sputum neutrophilia in large trials remains impractical, and a substantial proportion of patients with severe asthma cannot provide adequate sputum samples for measurement. Thus, the possibility that AZD5069 had no effect due to inadequate stratification of a truly neutrophilic phenotype, combined with only modest suppression of blood neutrophil counts, cannot be ruled out. Additionally, targeting only one among the many neutrophil chemoattractants might not be sufficient to have a notable effect.
www.thelancet.com/respiratory Published online August 26, 2016 http://dx.doi.org/10.1016/S2213-2600(16)30232-6
Michael Abbey/Science Photo Library
Neutrophilic asthma: a distinct target for treatment?
Lancet Respir Med 2016 Published Online August 26, 2016 http://dx.doi.org/10.1016/ S2213-2600(16)30232-6 See Online/Articles http://dx.doi.org/10.1016/ S2213-2600(16)30227-2
1
Comment
The identification of biomarkers of neutrophilic asthma that can be used in clinical trials and, ultimately, in the clinic is becoming imperative. Progress has been made in terms of the potential mechanisms underlying neutrophilic inflammation. Delayed neutrophil apoptosis, impaired macrophage phagocytosis, activation of the inflammasome pathway, and alterations in the airway microbiome have all been associated with neutrophilic airway inflammation.12,13 Several distinct neutrophil functional phenotypes with different effector functions, including immunomodulatory functions,14 that could form the basis of different endotypes of neutrophilic asthma, have also been reported. Saito and colleagues15 suggested that a raised concentration of the gastrotransmitter hydrogen sulphide in sputum could be a potential biomarker of neutrophilic asthma associated with airflow obstruction. It is hoped that the omics systems approaches will help to define the heterogeneity of the inflammatory pathways that underlie neutrophilic asthma.16 The challenge is to identify these endotypes of neutrophilic asthma so that patients can be stratified carefully for trials of neutrophil-specific therapies. Although the study of O’Byrne and colleagues was negative, the search for new treatments targeted towards well defined endotypes of neutrophilic non-eosinophilic asthma should continue with some optimism.
for research in asthma and chronic obstructive pulmonary disease from the European Innovative Medicines Initiative, GlaxoSmithKline, Pfizer, Medical Research Council (UK), and the National Institutes of Health (USA). 1 2
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4 5
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Kian Fan Chung National Heart and Lung Institute, Imperial College London, London SW3 6LY, UK; and Biomedical Research Unit, Royal Brompton and Harefield NHS Trust, London, UK. [email protected] I have received personal fees for advisory board membership from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Johnson and Johnson, Novartis, and Teva, honoraria for lectures from AstraZeneca, Merck, and Novartis, and grants
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14
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Chung KF. Asthma phenotyping: a necessity for improved therapeutic precision and new targeted therapies. J Intern Med 2016; 279: 192–204. Macedo P, Hew M, Torrego A, et al. Inflammatory biomarkers in airways of patients with severe asthma compared with non-severe asthma. Clin Exp Allergy 2009; 39: 1668–76. Jatakanon A, Uasuf C, Maziak W, Lim S, Chung KF, Barnes PJ. Neutrophilic inflammation in severe persistent asthma. Am J Respir Crit Care Med 1999; 160: 1532–39. Pavord ID, Brightling CE, Woltmann G, Wardlaw AJ. Non-eosinophilic corticosteroid unresponsive asthma. Lancet 1999; 353: 2213–14. Fahy JV, Kim KW, Liu J, Boushey HA. Prominent neutrophilic inflammation in sputum from subjects with asthma exacerbation. J Allergy Clin Immunol 1995; 95: 843–52. Manni ML, Trudeau JB, Scheller EV, et al. The complex relationship between inflammation and lung function in severe asthma. Mucosal Immunol 2014; 7: 1186–98. O’Byrne PM, Metev H, Puu M, et al. Efficacy and safety of a CXCR2 antagonist, AZD5069, in patients with uncontrolled persistent asthma: a randomised, double-blind, placebo-controlled trial. Lancet Respir Med 2016; published online Aug 26. http://dx.doi. org/10.1016/S2213-2600(16)30227-2. Wenzel SE, Barnes PJ, Bleecker ER, et al. A randomized, double-blind, placebo-controlled study of tumor necrosis factor-alpha blockade in severe persistent asthma. Am J Respir Crit Care Med 2009; 179: 549–58. Busse WW, Holgate S, Kerwin E, et al. Randomized, double-blind, placebo-controlled study of brodalumab, a human anti-IL-17 receptor monoclonal antibody, in moderate to severe asthma. Am J Respir Crit Care Med 2013; 188: 1294–302. Brusselle GG, VanderStichele C, Jordens P, et al. Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax 2013; 68: 322–29. Hastie AT, Moore WC, Li H, et al. Biomarker surrogates do not accurately predict sputum eosinophil and neutrophil percentages in asthmatic subjects. J Allergy Clin Immunol 2013; 132: 72–80. Simpson JL, Daly J, Baines KJ, et al. Airway dysbiosis: Haemophilus influenzae and Tropheryma in poorly controlled asthma. Eur Respir J 2016; 47: 792–800. Zhang Q, Cox M, Liang Z, et al. Airway microbiota in severe asthma and relationship to asthma severity and phenotypes. PloS One 2016; 11: e0152724. Bruijnzeel PL, Uddin M, Koenderman L. Targeting neutrophilic inflammation in severe neutrophilic asthma: can we target the disease-relevant neutrophil phenotype? J Leukoc Biol 2015; 98: 549–56. Saito J, Zhang Q, Hui C, et al. Sputum hydrogen sulfide as a novel biomarker of obstructive neutrophilic asthma. J Allergy Clin Immunol 2013; 131: 232–34. Zhang H, Gustafsson M, Nestor C, Chung KF, Benson M. Targeted omics and systems medicine: personalising care. Lancet Respir Med 2014; 2: 785–87.
www.thelancet.com/respiratory Published online August 26, 2016 http://dx.doi.org/10.1016/S2213-2600(16)30232-6
Over the past decade, eosinophilic asthma, which is characterised by raised circulating eosinophil counts, has become an established phenotype. These patients are at risk of exacerbations but respond to corticosteroid therapy. Furthermore, biological therapies targeted at interleukin 5, a T-helper-2 cytokine important in the terminal differentiation and activation of eosinophils, have been effective in patients with severe and recurrent exacerbations, which further supports eosinophilic asthma as a distinct phenotype.1 By contrast, the neutrophilic non-eosinophilic asthma phenotype remains less-well defined although 50% of patients with symptomatic asthma are thought to have it. This phenotype is described as high neutrophil counts in sputum ranging from 40% to 76% of sputum cells. Increased neutrophil counts in sputum have been associated with severe asthma, corticosteroid insensitivity, and chronic airflow obstruction,2–4 and are seen during acute exacerbations.5 These associations have led to the notion that neutrophil infiltration into the airways might have a crucial role in the pathophysiological processes underlying severe asthma. Another possibility, however, is that increased numbers of neutrophils in the airways could be the result of infection, exposure to air pollutants, or treatment with corticosteroids—particularly oral corticosteroids, which are used on a daily basis by more than 40% of patients with severe asthma—and might merely be innocent bystanders. Various neutrophilic chemokines have been implicated in neutrophil recruitment in patients with severe neutrophilic asthma, including GROα, interleukin 8, CXCL10, and CCL2, with patients having raised concentrations of these chemokines in sputum.2,6 It is in this context that Paul O’Byrne and colleagues,7 in The Lancet Respiratory Medicine, explore the role for a CXCR2 antagonist in the treatment of patients with uncontrolled persistent asthma. AZD5069 is a CXCR2 chemokine receptor antagonist that blocks the effects of interleukin 8. The researchers did a 6-month phase 2b study in 640 patients with uncontrolled persistent asthma who were taking a combination of high-dose inhaled corticosteroids and long-acting β₂ agonists. Neutrophilic asthma was defined as eosinophil counts in blood lower than 0·5 × 10⁹/L, IgE concentrations in
serum lower than 750 kIU/L, and neutrophil counts in blood greater than 2·7 × 10⁹/L. Patients were randomly assigned to receive 5, 15, or 45 mg oral AZD5069 twice daily or matched placebo as add-on therapy to standard treatment. Although, as expected, AZD5069 reduced mean blood neutrophil counts, by up to 20·5% after 6 months of treatment with the 45 mg dose, no difference was seen compared with placebo in the rate of severe exacerbations, asthma symptoms, or lung function. These negative results follow on from those seen in studies of inhibitors of the neutrophilic pathway in patients with moderate to severe asthma, including golimumab, an antibody against TNFα,8 brodalumab, an antibody against interleukin 17 receptor,9 and the macrolide antibiotic, azithromycin.10 Those studies were not stratified by inflammatory phenotype; however, the importance of stratification was illustrated in the azithromycin study, in which a predefined subgroup with non-eosinophilic severe asthma (eosinophil counts in blood <0·2×10⁹/L) showed reductions in the rates of severe exacerbations and lower respiratory tract infections with azithromycin treatment, whereas there was no effect when the non-stratified group was analysed as a whole.10 In the study of O’Byrne and colleagues,7 although the neutrophilic asthma phenotype was based on the presence of high blood neutrophil counts, the eosinophil count cutoff was high (0·5×10⁹/L) and, therefore, some patients with eosinophilic asthma might have been included. Additionally, neutrophil counts in blood and sputum are weakly correlated and poorly predictive of sputum neutrophilia,11 which suggests that blood neutrophil count might not be a good marker of neutrophilic asthma. As noted by O’Byrne and colleagues,7 though, the measurement of sputum neutrophilia in large trials remains impractical, and a substantial proportion of patients with severe asthma cannot provide adequate sputum samples for measurement. Thus, the possibility that AZD5069 had no effect due to inadequate stratification of a truly neutrophilic phenotype, combined with only modest suppression of blood neutrophil counts, cannot be ruled out. Additionally, targeting only one among the many neutrophil chemoattractants might not be sufficient to have a notable effect.
www.thelancet.com/respiratory Published online August 26, 2016 http://dx.doi.org/10.1016/S2213-2600(16)30232-6
Michael Abbey/Science Photo Library
Neutrophilic asthma: a distinct target for treatment?
Lancet Respir Med 2016 Published Online August 26, 2016 http://dx.doi.org/10.1016/ S2213-2600(16)30232-6 See Online/Articles http://dx.doi.org/10.1016/ S2213-2600(16)30227-2
1
Comment
The identification of biomarkers of neutrophilic asthma that can be used in clinical trials and, ultimately, in the clinic is becoming imperative. Progress has been made in terms of the potential mechanisms underlying neutrophilic inflammation. Delayed neutrophil apoptosis, impaired macrophage phagocytosis, activation of the inflammasome pathway, and alterations in the airway microbiome have all been associated with neutrophilic airway inflammation.12,13 Several distinct neutrophil functional phenotypes with different effector functions, including immunomodulatory functions,14 that could form the basis of different endotypes of neutrophilic asthma, have also been reported. Saito and colleagues15 suggested that a raised concentration of the gastrotransmitter hydrogen sulphide in sputum could be a potential biomarker of neutrophilic asthma associated with airflow obstruction. It is hoped that the omics systems approaches will help to define the heterogeneity of the inflammatory pathways that underlie neutrophilic asthma.16 The challenge is to identify these endotypes of neutrophilic asthma so that patients can be stratified carefully for trials of neutrophil-specific therapies. Although the study of O’Byrne and colleagues was negative, the search for new treatments targeted towards well defined endotypes of neutrophilic non-eosinophilic asthma should continue with some optimism.
for research in asthma and chronic obstructive pulmonary disease from the European Innovative Medicines Initiative, GlaxoSmithKline, Pfizer, Medical Research Council (UK), and the National Institutes of Health (USA). 1 2
3
4 5
6
7
8
9
10
11
12
13
Kian Fan Chung National Heart and Lung Institute, Imperial College London, London SW3 6LY, UK; and Biomedical Research Unit, Royal Brompton and Harefield NHS Trust, London, UK. [email protected] I have received personal fees for advisory board membership from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Johnson and Johnson, Novartis, and Teva, honoraria for lectures from AstraZeneca, Merck, and Novartis, and grants
2
14
15
16
Chung KF. Asthma phenotyping: a necessity for improved therapeutic precision and new targeted therapies. J Intern Med 2016; 279: 192–204. Macedo P, Hew M, Torrego A, et al. Inflammatory biomarkers in airways of patients with severe asthma compared with non-severe asthma. Clin Exp Allergy 2009; 39: 1668–76. Jatakanon A, Uasuf C, Maziak W, Lim S, Chung KF, Barnes PJ. Neutrophilic inflammation in severe persistent asthma. Am J Respir Crit Care Med 1999; 160: 1532–39. Pavord ID, Brightling CE, Woltmann G, Wardlaw AJ. Non-eosinophilic corticosteroid unresponsive asthma. Lancet 1999; 353: 2213–14. Fahy JV, Kim KW, Liu J, Boushey HA. Prominent neutrophilic inflammation in sputum from subjects with asthma exacerbation. J Allergy Clin Immunol 1995; 95: 843–52. Manni ML, Trudeau JB, Scheller EV, et al. The complex relationship between inflammation and lung function in severe asthma. Mucosal Immunol 2014; 7: 1186–98. O’Byrne PM, Metev H, Puu M, et al. Efficacy and safety of a CXCR2 antagonist, AZD5069, in patients with uncontrolled persistent asthma: a randomised, double-blind, placebo-controlled trial. Lancet Respir Med 2016; published online Aug 26. http://dx.doi. org/10.1016/S2213-2600(16)30227-2. Wenzel SE, Barnes PJ, Bleecker ER, et al. A randomized, double-blind, placebo-controlled study of tumor necrosis factor-alpha blockade in severe persistent asthma. Am J Respir Crit Care Med 2009; 179: 549–58. Busse WW, Holgate S, Kerwin E, et al. Randomized, double-blind, placebo-controlled study of brodalumab, a human anti-IL-17 receptor monoclonal antibody, in moderate to severe asthma. Am J Respir Crit Care Med 2013; 188: 1294–302. Brusselle GG, VanderStichele C, Jordens P, et al. Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax 2013; 68: 322–29. Hastie AT, Moore WC, Li H, et al. Biomarker surrogates do not accurately predict sputum eosinophil and neutrophil percentages in asthmatic subjects. J Allergy Clin Immunol 2013; 132: 72–80. Simpson JL, Daly J, Baines KJ, et al. Airway dysbiosis: Haemophilus influenzae and Tropheryma in poorly controlled asthma. Eur Respir J 2016; 47: 792–800. Zhang Q, Cox M, Liang Z, et al. Airway microbiota in severe asthma and relationship to asthma severity and phenotypes. PloS One 2016; 11: e0152724. Bruijnzeel PL, Uddin M, Koenderman L. Targeting neutrophilic inflammation in severe neutrophilic asthma: can we target the disease-relevant neutrophil phenotype? J Leukoc Biol 2015; 98: 549–56. Saito J, Zhang Q, Hui C, et al. Sputum hydrogen sulfide as a novel biomarker of obstructive neutrophilic asthma. J Allergy Clin Immunol 2013; 131: 232–34. Zhang H, Gustafsson M, Nestor C, Chung KF, Benson M. Targeted omics and systems medicine: personalising care. Lancet Respir Med 2014; 2: 785–87.
www.thelancet.com/respiratory Published online August 26, 2016 http://dx.doi.org/10.1016/S2213-2600(16)30232-6