Editorial
Neutrophilic Asthma
Asma neutrofílica
Airways Disease, National Heart & Lung Institute, Imperial College London, London, UK
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Adcock, Sharon E. Mumby" "autores" => array:2 [ 0 => array:4 [ "nombre" => "Ian M." "apellidos" => "Adcock" "email" => array:1 [ 0 => "ian.adcock@imperial.ac.uk" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "Sharon E." "apellidos" => "Mumby" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Airways Disease, National Heart & Lung Institute, Imperial College London, London, UK" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Asma neutrofílica" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">The goal of systems or personalized medicine is to deliver the optimal drug to the right patient at the right time.<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">1,2</span></a> A prerequisite for this is the correct identification of asthma clinical phenotypes that possess mechanisms that can be targeted by specific drugs. Eosinophilic asthma is one such phenotype which is characterized by elevated levels of circulating eosinophils. These patients have an underlying type 2 T-helper cell (Th2) mechanism, are more responsive to treatment with inhaled corticosteroids (ICS) but conversely appear more susceptible to exacerbations.<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">1,2</span></a> The appreciation of the Th2-based driver mechanism of these patients has driven the use of biological therapies targeted Th2 cytokines. For example, anti-IL-5-directed drugs used to block eosinophil differentiation and activation are effective in patients with high blood eosinophils, severe and recurrent exacerbations already requiring high dose ICS and oral corticosteroids (OCS) <a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">1,2</span></a>. Unfortunately, only 40-50% of asthmatics have this phenotype and there is a need to define non-Th2 asthma along with their associated driver mechanisms.</p><p id="par0010" class="elsevierStylePara elsevierViewall">Neutrophilic asthma was first reported in bronchial biopsies <a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">3</span></a>but is more often defined as patients with high (40-70%) sputum neutrophil counts. Sputum neutrophilia is linked to severe asthma, a relative lack of response to corticosteroid therapy and chronic airflow obstruction, <a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">3</span></a>and is reported to occur in acute exacerbations<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">3</span></a>. A neutrophilic asthma phenotype may arise from the presence of enhanced levels of neutrophilic chemokines such as GROα, interleukin 8, CXCL10, and CCL2 which are all elevated in sputum of these patients.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">3</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">However, a number of clinical trials directed against neutrophil-associated mediators have not been successful in moderate to severe asthma. These studies include an antibody against TNFα (golimumab), an anti-IL-17 receptor antibody (brodalumab) and with a CXCR2 antagonist.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">3</span></a> In the latter study, involving 640 patients with uncontrolled persistent asthma, treatment for 6 months with the CXCR2 antagonist AZD5069, that blocks the effects of interleukin 8, had no effect on the rate of severe exacerbations, asthma symptoms, or lung function compared with placebo despite significantly reducing mean blood neutrophil counts.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">4</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">A recent study, the AMAZES study, from Gibson and colleagues <a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">5</span></a>examined the effect of 500<span class="elsevierStyleHsp" style=""></span>mg azithrpmycin or placebo on 420 adults with uncontrolled persistent asthma despite the use of ICS and long-acting bronchodilator therapy over 48 weeks. In this study, azithromycin reduced asthma exacerbations and significantly improved asthma-related quality of life irrespective of asthma phenotype. These results were in contrast to an earlier study (AZISAST) where evidence for a preferential effect of azithromycin on severe exacerbations and on the rate of lower respiratory tract infections in neutrophilic asthma was observed.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">6</span></a> The AZiSAST study compared 250<span class="elsevierStyleHsp" style=""></span>mg azithromycin and placebo over 26 weeks in 109 subjects and also had different inclusion criteria and inflammatory granulocyte classifications which may account for the difference in outcomes. However, the results regarding lower respiratory tract infections in non-eosinophilic asthmatics were similar in the two studies.</p><p id="par0025" class="elsevierStylePara elsevierViewall">These data on the beneficial effect of azithromycin in both eosinophilic and non-eosiniphilic severe asthma correspond to earlier data in murine models of severe steroid refractory allergic asthma whereby clarithromycin suppressed inflammation and airway hyperresponsiveness by distinct mechanisms (reducing Th2-driven eosinophilia and suppression of IL-17 and TNFα) depending upon the models used.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">7</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">This may suggest that that neutrophils <span class="elsevierStyleItalic">per se</span> are not driving a distinct asthma phenotype since raised levels of sputum neutrophils may also result from sub-clinical or clinical infection and environmental pollution.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">8</span></a> Furthermore, long term high-dose ICS or OCS use may prevent neutrophil cell death resulting in an apparent neutrophilic disease. However, it is evident that blood and sputum neutrophil counts are only weakly correlated and poorly predictive of sputum neutrophilia.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">8</span></a> Stratification of patients according to blood neutrophils is, therefore, less than optimal and a better marker of neutrophilic asthma is required. Poor patient stratification may result in the failure of many of these trials in neutrophilic asthma as a true airway neutrophilic phenotype was not selected. In addition, the complexity of the chemokine/chemokine receptor system <a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">9</span></a>means that targeting a single neutrophil chemoattractant may not be sufficient to have a notable effect.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Analysis of sputum cell transcriptomics between severe and non-severe asthma highlighted the importance of inflammasome activation in neutrophilic asthmatics in the absence of overt infection <a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">10</span></a>. Inhibition of inflammasome activation in a mouse model of severe asthma indicated cross-talk between eosinophilic and neutrophilic asthma. This was confirmed by Hansbro and colleagues who demonstrated that NLRP3 and IL-1β expression correlated with neutrophilic inflammation, disease severity and steroid resistance in asthma and these features could be induced by IL-1β overexpression in a mouse model of asthma.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">11</span></a> In addition, IL-1β-induced steroid-resistant airway hyperresponsiveness was suppressed by neutrophil depletion.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Differential sputum cell transcriptomics has also implicated neutrophil-derived TCN1 and MMP9, mucins and oxidative stress response genes as being important in severe neutrophilic asthma.<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">12</span></a> A disease signature, closely associated with sputum T-cells, was defined which included IL-17-inducible chemokines (CXCL1, CXCL2, CXCL3, IL8, CSF3) and neutrophil chemoattractants (IL8, CCL3, LGALS3) which again highlighted the key role for bacterial infection via TLR2 activation in this asthma phenotype. These data are reinforced by the finding that the sputum microbiome in a small number of neutrophilic asthmatics was less diverse and more dissimilar compared with that observed in eosinophilic asthma and correlated with sputum neutrophil cell counts.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">13</span></a> Neutrophilic asthma was associated with a relatively greater abundance of pathogenic taxa and a lower expression of Streptococcus, Gemella, and Porphyromonas taxa. The data suggests that differences in microbiota composition might influence neutrophilic asthma and impact upon antimicrobial and steroid responses.</p><p id="par0045" class="elsevierStylePara elsevierViewall">It is evident that current biomarkers of neutrophilic asthma are not suitable for use in clinical trials and the discovery of good biomarkers is essential. Sputum colour has been proposed as a biomarker to identify patients with neutrophilic asthma.<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">14</span></a> Although significant, the sensitivity and specificity are below 80% and still requires the production of sputum which is an issue with many subjects with severe asthma. More importantly, Alam and colleagues found 52 biomolecules in BAL fluid that differentiated refractory asthma (RA) from non-RA subjects.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">15</span></a> 13 out of these 52 molecules correlated with BAL neutrophilia and, in addition, five serum inflammatory analytes (growth and differentiation factor 15 (GDF-15), human epididymis protein 4, MMP7, tetranectin, and von Willebrand factor) were associated with infection-negative neutrophilic RA. These results are exciting and need to be confirmed. Blood biomarkers and non-invasive measures such as exhaled volatile organic compounds (VOCs) should also be investigated.</p><p id="par0050" class="elsevierStylePara elsevierViewall">In addition, it will be important to distinguish the presence of neutrophils with distinct functional phenotypes and immunomodulatory functions.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">3</span></a> Despite this, the mechanisms underlying neutrophilic asthma as demonstrated above are becoming clear and include delayed neutrophil apoptosis, impaired macrophage phagocytosis, activation of the inflammasome pathway, alterations in the airway microbiome and distinct neutrophil subtypes.<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">1,3</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Systems medicine, which extends beyond a simple omics analysis, combining deep clinical phenotyping is expected to define the many inflammatory pathways that underlie neutrophilic asthma.<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">1,3</span></a> The present challenge is to develop the means to easily identify these sub-phenotypes of neutrophilic asthma in order to stratify patients and enhance the chances of success in clinical trials using anti-neutrophil therapies.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Funding</span><p id="par0060" class="elsevierStylePara elsevierViewall">IMA is supported by the EU- Innovative Medicines Initiative Joint Undertaking project U-BIOPRED (115010) and is a member of Interuniversity Attraction Poles Program-Belgian State-Belgian Science Policy- project P7/30.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Conflicts of Interests</span><p id="par0065" class="elsevierStylePara elsevierViewall">There are no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Funding" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Conflicts of Interests" ] 2 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:15 [ 0 => array:3 [ "identificador" => "bib0080" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:1 [ "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "K.F. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 3 | 1 | 4 |
| 2024 October | 44 | 21 | 65 |
| 2024 September | 39 | 23 | 62 |
| 2024 August | 52 | 39 | 91 |
| 2024 July | 39 | 22 | 61 |
| 2024 June | 74 | 26 | 100 |
| 2024 May | 78 | 26 | 104 |
| 2024 April | 52 | 28 | 80 |
| 2024 March | 43 | 20 | 63 |
| 2024 February | 25 | 24 | 49 |
| 2023 March | 11 | 2 | 13 |
| 2023 February | 43 | 18 | 61 |
| 2023 January | 31 | 25 | 56 |
| 2022 December | 52 | 36 | 88 |
| 2022 November | 47 | 22 | 69 |
| 2022 October | 48 | 39 | 87 |
| 2022 September | 30 | 21 | 51 |
| 2022 August | 37 | 37 | 74 |
| 2022 July | 28 | 40 | 68 |
| 2022 June | 26 | 31 | 57 |
| 2022 May | 37 | 28 | 65 |
| 2022 April | 28 | 28 | 56 |
| 2022 March | 26 | 30 | 56 |
| 2022 February | 36 | 24 | 60 |
| 2022 January | 40 | 29 | 69 |
| 2021 December | 35 | 48 | 83 |
| 2021 November | 52 | 40 | 92 |
| 2021 October | 96 | 64 | 160 |
| 2021 September | 54 | 53 | 107 |
| 2021 August | 42 | 44 | 86 |
| 2021 July | 31 | 23 | 54 |
| 2021 June | 38 | 39 | 77 |
| 2021 May | 48 | 46 | 94 |
| 2021 April | 102 | 96 | 198 |
| 2021 March | 82 | 37 | 119 |
| 2021 February | 56 | 25 | 81 |
| 2021 January | 67 | 21 | 88 |
| 2020 December | 37 | 19 | 56 |
| 2020 November | 55 | 21 | 76 |
| 2020 October | 134 | 28 | 162 |
| 2020 September | 149 | 15 | 164 |
| 2020 August | 92 | 19 | 111 |
| 2020 July | 79 | 26 | 105 |
| 2020 June | 45 | 7 | 52 |
| 2020 May | 38 | 18 | 56 |
| 2020 April | 43 | 14 | 57 |
| 2020 March | 29 | 8 | 37 |
| 2020 February | 205 | 37 | 242 |
| 2020 January | 42 | 22 | 64 |
| 2019 December | 76 | 22 | 98 |
| 2019 November | 64 | 26 | 90 |
| 2019 October | 67 | 41 | 108 |
| 2019 September | 51 | 21 | 72 |
| 2019 August | 45 | 30 | 75 |
| 2019 July | 41 | 19 | 60 |
| 2019 June | 88 | 34 | 122 |
| 2019 May | 54 | 20 | 74 |
| 2019 April | 53 | 27 | 80 |
| 2019 March | 46 | 20 | 66 |
| 2019 February | 49 | 34 | 83 |
| 2019 January | 77 | 30 | 107 |
| 2018 December | 38 | 25 | 63 |
| 2018 November | 44 | 29 | 73 |
| 2018 October | 75 | 30 | 105 |
| 2018 September | 3 | 0 | 3 |
| 2018 April | 1 | 3 | 4 |
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