Targeting Immune Pathways for Therapy in Asthma and ChronicObstructive Pulmonary DiseaseGuy Brusselle1,2 and Ken Bracke1
1Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium; and 2Departments of Epidemiology and RespiratoryMedicine, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
Abstract
Asthma and chronic obstructive pulmonary disease (COPD) arehighly prevalent chronic inflammatory diseases of the airways, withdifferences in etiology, pathogenesis, immunologic mechanisms,clinical presentation, comorbidities, prognosis, and response totreatment. In mild to moderate early-onset allergic asthma, theTh2-driven eosinophilic airway inflammation and the ensuingdisease can be well controlled with maintenance treatment withinhaled corticosteroids (ICS). In real-life settings, asthma controlcan be improved by facilitating adherence to ICS treatment andby optimizing inhaler technique. In patients with uncontrolled severeasthma, old and novel therapies targeting specific immunologicpathways should be added according to the underlying endotype/
phenotype. InCOPD, there is a high unmet need for safe and effectiveantiinflammatory treatments that not only prevent exacerbationsbut also have a beneficial impact on the course of the disease andimprove survival. Although several new approaches aim to target thechronic neutrophilic pulmonary inflammation per se in patientswith COPD, strategies that target the underlying causes of thepulmonary neutrophilia (e.g., smoking, chronic infection, andoxidative stress) might be more successful. In both chronic airwaydiseases (especially in more difficult, complex cases), the choiceof the optimal treatment should be based not only on arbitraryclinical labels but also on the underlying immunopathology.
(Received in original form March 18, 2014; accepted in final form June 17, 2014 )
Although G.B. is currently guideline director of the European Respiratory Society, this manuscript only reflects his personal opinions and ideas.
Correspondence and requests for reprints should be addressed to Guy Brusselle, M.D., Ph.D., Ghent University Hospital, Respiratory Medicine, De Pintelaan185, B-9000 Ghent, Belgium. E-mail: [email protected]
Asthma and chronic obstructive pulmonarydisease (COPD) are chronic inflammatorydiseases of the airways, which shareclinical symptoms (shortness of breath,wheezing, coughing, and sputum production),pathophysiological mechanisms (airflowlimitation and bronchial hyperresponsiveness),and pathogenetic mechanisms (i.e.,interactions between environmentalexposures and genetic susceptibility) (1).Although asthma has been classicallyconsidered as caused by an allergiceosinophilic airway inflammation, mostfrequently starting in early life (childhoodand adolescence), it has become evidentthat asthma is a very heterogeneoussyndrome, encompassing other phenotypesof asthma, such as nonallergic asthma,noneosinophilic asthma (characterized by
neutrophilic or paucigranulocytic airwayinflammation), and asthma that startsonly in adulthood (adult-onset/late-onsetasthma) (2–4). Unfortunately, somepatients with asthma do smoke and therebyrespond less well to maintenance treatmentwith inhaled corticosteroids (ICS).
At the other end of the spectrum ofchronic airway disease, COPD has beenclassically defined as an irreversible airflowlimitation in smokers or ex-smokers, whichis associated with chronic neutrophilicinflammation of the small airways(bronchiolitis) and progressive destructionof the lung parenchyma (emphysema) (5).However, COPD is also a heterogeneousdisease that encompasses multiplephenotypes (e.g., airway-predominant vs.emphysema-predominant phenotypes)
and can occur in never-smokers (causedby exposure to biomass fuel smoke,outdoor air pollution, and/or occupationalexposures) (6, 7). Moreover, the airflowlimitation is partially reversible inapproximately one-half of the patientswith COPD (8). In this opinion paper,we focus on asthma in nonsmokingadults and on COPD in (ex)smokers,because most randomized clinical trials(RCTs) systematically exclude currentsmokers (or ex-smokers with a smokinghistory of .10 pack-years) in trials ofasthma, and never-smokers (or smokerswith a smoking history of ,10 pack-years)in trials of COPD. Apparently, forpharmaceutical companies and regulators,the magic number of 10 (pack-years ofsmoking) is the critical cut-off point for
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the differential diagnosis between asthmaand COPD.
Asthma
Asthma is characterized by chronic airwayinflammation, which is associated withbronchial hyperresponsiveness, leading tovariable airflow limitation and respiratorysymptoms (cough, wheezing, chesttightness, and/or shortness of breath) onexposure to specific allergens or nonspecifictriggers. In the past decades, asthma hasbeen considered as a homogeneous diseasecaused by an allergen-induced, Th2-driveneosinophilic airway inflammation, whichhas been modeled extensively in mice usingovalbumin or house dust mite as allergens(9, 10). However, clinical and translationalresearch in recent years has demonstratedthat asthma is a heterogeneous diseaseencompassing many different endotypesand phenotypes (Figure 1) (2, 3). Althoughseveral classification schemes of asthmahave been proposed, for the purpose ofthis paper we will focus on the differentinflammatory phenotypes of asthma,encompassing eosinophilic asthma,neutrophilic asthma, mixed granulocyticasthma, and paucigranulocytic asthma.Importantly, whereas allergy has beenregarded as the main driver in asthmapathogenesis, it has become clear thata large proportion of adult patients,even those with eosinophilic asthma,are nonallergic (defined by negative skinprick tests and serum allergen-specificradioallergosorbent tests) (11, 12).
The current mainstay treatment ofpersistent asthma is inhaled corticosteroids(ICS), with or without long-acting b2-agonists (LABA). Treatment with ICS for1 month or more significantly reduces thepathological signs of airway inflammationin asthma, decreasing the number ofTh2 lymphocytes and eosinophils andimproving progressively the bronchialhyperresponsiveness with prolongedtreatment (13, 14). Classical RCTs haveprovided overwhelming evidence of theefficacy and safety of ICS in children andadults with persistent asthma, leading towell-controlled disease in the majorityof patients with mild to moderate asthma.However, observational real-life studiesthroughout the world have shownthat many patients with asthma haveuncontrolled disease due to a combination
of factors: mainly noncompliance withmaintenance treatment (ICS), incorrectinhalation technique, the presence ofcomorbidities (e.g., chronic rhinosinusitis,gastroesophageal reflux, obesity, obstructivesleep apnea syndrome, and depression),and persistent exposure to allergens and/orirritants (e.g., cigarette smoke) (15, 16).The implication of this discrepancy isthat—at the population level—major gainsin asthma control could be obtained byfacilitating adherence to chronic ICStreatment and by optimizing inhalationdevices and techniques (17). However,a subgroup of patients with refractorysevere asthma remain uncontrolled despiteoptimal adherence to treatment with high-dose ICS and even oral corticosteroids,implicating a high unmet medical need.
Although ICS are an efficaciousantiinflammatory treatment in patientswith mild to moderate asthma, they do notmodify the course of the disease and thusdo not cure asthma. In the past decade,several large RCTs and Cochrane reviewshave proven that (subcutaneous) specificimmunotherapy with the appropriateallergen is efficacious and safe in well-selected patients with allergic rhinitis.Due to the increased risk of severeallergic reactions, including anaphylaxisand severe asthma attacks, specific allergenimmunotherapy has been contraindicatedin patients with uncontrolled asthma.
Targeting specific immune pathways isbecoming an attractive approach in patientswith uncontrolled severe asthma (9).Because severe asthma is a heterogeneoussyndrome, the specific immunologicadd-on therapies (on top of high-doseICS1LABA) should be targeted to theappropriate severe asthma phenotype(18). The classic example is the anti-IgEmonoclonal antibody omalizumab, whichis indicated in patients with severe allergicasthma with frequent exacerbations andpersistent airflow limitation. Omalizumabhas been shown to attenuate eosinophilicairway inflammation in subjects withallergic asthma and to reduce the frequencyof exacerbations in severe allergic asthma(19). Moreover, an increased fractionalexcretion of nitric oxide in the exhaledair, an increased blood eosinophilia,and increased serum levels of periostin,a protein produced by airway epithelial cellsunder the influence of the Th2-cytokineIL-13, are predictors of response totreatment with omalizumab (20). In
patients with refractory eosinophilicasthma, add-on treatment with the anti–IL-5 monoclonal antibody mepolizumabhas been shown to significantly reduce therate of severe asthma exacerbations (11,21). Importantly, approximately half ofthe patients with severe eosinophilic asthmain the Does Ranging Efficacy And safetywith Mepolizumab in severe asthma(DREAM) study were nonallergic,suggesting that besides the classical Th2pathway other immunologic mechanisms,such as the epithelial–innate lymphoid celltype 2 (ILC2) pathway, might be involvedin this asthma phenotype (12). We putforward the hypothesis that patientswith adult-onset (late-onset), nonallergicsevere eosinophilic asthma with repetitiveexacerbations are the best respondersto add-on treatment with anti–IL-5 oranti–IL-13 monoclonal antibodies. Ourhypothesis that innate lymphocytes suchas ILC2s and natural killer T cells driveeosinophilic airway inflammation insevere nonallergic asthma is based onthe following observations: (1) patientswith this severe asthma phenotype havefrequently chronic rhinosinusitis withnasal polyps as comorbidity, (2) ILC2sare strongly increased in eosinophilicnasal polyposis, and (3) ILC2s are ableto produce high amounts of IL-5 andIL-13 (22, 23). However, this hypothesisneeds to be tested appropriately by basic,translational, and clinical research inpatients with (nonallergic and allergic)severe asthma. If our hypothesis isconfirmed, the ILC2s pathway mightexplain the unusual pharmacology ofnonallergic severe asthma, which is poorlyresponding to topical treatment withICS but responds well to systemiccorticosteroids and the cytokine blockersanti–IL-5 and anti–IL-13.
Because the monoclonal antibodydupilumab targets the IL-4a receptor,which is a subunit common to the IL-4and IL-13 receptors, it has the abilityto interfere with both the Th2 pathway(including IL-4 signaling and IgE synthesis)as well as the ILC2 pathway. In an ICS-tapering RCT, dupilumab significantlyprevented mild asthma exacerbationscompared with placebo (24). However,at least two caveats should be underlinedbefore extrapolating these promising resultsto the treatment of patients with severeasthma in clinical practice. First, thepathogenesis of exacerbations elicited by
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reducing and stopping ICS and LABA inpatients with (partially) controlled asthmamight be fundamentally different fromnaturally occurring asthma exacerbationsin patients on persistent ICS1LABAtreatment. Second, because we hypothesizethat Th2 lymphocytes are very sensitiveto ICS, in contrast to ILC2s, the relativecontribution of these immunologicmechanisms/pathways might differaccording to whether the patient ison high-dose ICS or not.
In patients with neutrophilic asthma,add-on treatment with the macrolideazithromycin has been shown to decreasethe rate of exacerbations (25). In addition,a metaanalysis of RCTs of macrolidesin moderate to severe asthma hasdemonstrated that macrolides improvethe quality of life compared with placebo(26). These clinical data are in agreementwith the proven efficacy and safety ofmacrolides in other neutrophilic chronicairway diseases, such as cystic fibrosis,
non–cystic fibrosis bronchiectasis,diffuse panbronchiolitis, COPD, andbronchiolitis obliterans after lungtransplantation. However, the fact thatneutrophilic airway inflammation appearsto be a predictor of response to treatmentwith macrolides does not prove thatneutrophils are the main target in thesediseases. First, more specific antineutrophil-directed therapies such as brodalumab,a human anti–IL-17 receptor monoclonalantibody, have failed in patients withmoderate to severe asthma, although theinvestigators did not enrich the enrolledpatient population for the neutrophilicphenotype (27). Second, macrolideshave both immunomodulatory,antiinflammatory effects and antibioticeffects, encompassing the direct killingof microbes (e.g., Haemophilus influenzae),the prevention of biofilm formationthrough interfering with quorum sensing(e.g., Pseudomonas aeruginosa), and thestimulation of phagocytosis of microbes
by alveolar macrophages (28). Becausepopulation antimicrobial resistance dueto chronic treatment with macrolides is aconcern, the development of nonantibioticmacrolides is an attractive approach (29).It will be crucial to compare the effectsof the newer nonantibiotic macrolides insevere (neutrophilic) asthma not only withplacebo but also with the classical macrolideantibiotics, such as azithromycin. Ifazithromycin appears to be more efficaciousthan the newly developed nonantibioticmacrolide(s), this would suggest that thechronic bacterial colonization and infectionof the lower airways with microbes suchas H. influenzae and Haemophilusparainfluenzae is contributing to thepathogenesis of severe asthma.
COPD
The mainstay of current therapy for COPDis long-acting bronchodilators, including
allergen
epithelium
mast cell
lgE
TSLPTSLPP
TSLP
MHCII
TCR
IL-25
IL-33
IL-33
ILC2
IL-1
3
IL-4
, IL-1
3
goblet cell
pollutants, microbes, glycolipids
Th17 cellIL-17R
IL-17A
CXCL8GM-CSF
NKT cells
eosinophil
naive T-cell
B-cell
Th2 cell
IL-5
IL-13 IL-1
3
IL-13
IL-5
β2-adrenergic receptor
smooth muscle cell
ICS ± LABA
add-on treatment:
• anti-lgE (omalizumab)
• anti-lL-13
• anti-lL-4Rα (dupilumab)
ICS ± LABA
add-on treatment:
• anti-lL-5 (mepolizumab)
• anti-lL-13
• anti-lL-4Rα (dupilumab)
ICS ± LABA
add-on treatment:
• macrolides (azithromycin)
• anti-lL-17
• anti-lL-17R (brodalumab)
neutrophil
allergic eosinophilicasthma
nonallergic eosinophilicasthma
neutrophilicasthma
Figure 1. Simplified scheme of three different types of chronic airway inflammation in patients with asthma. In allergic eosinophilic asthma, Th2lymphocytes and mast cells drive eosinophilic airway inflammation in an allergen-specific, IgE-dependent manner. In nonallergic eosinophilic asthma,innate lymphocytes such as natural killer T cells (NKT cells) and innate lymphoid cells type 2 (ILC2) might contribute to airway eosinophilia via theproduction of IL-5. The mechanisms underlying neutrophilic asthma need to be elucidated, but the IL-17 pathway and CXCL8 have been associatedwith airway neutrophilia. GM-CSF = granulocyte/macrophage colony-stimulating factor; ICS = inhaled corticosteroids; LABA = long-acting b2-agonist;MHC = major histocompatibility complex; TCR = T cell receptor; TSLP = thymic stromal lymphopoietin.
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LABAs and long-acting muscarinic receptorantagonists (30). Although LABAs andlong-acting muscarinic receptor antagonistshave additive effects on improvementof lung function and symptoms inpatients with COPD, they do not affectthe underlying pulmonary inflammation(Figure 2). Although a longitudinalstudy with bronchial biopsies hasdemonstrated that combination therapywith ICS and LABA significantly reducedthe number of CD81 T lymphocytes inthe bronchial mucosa of patients withCOPD, the antiinflammatory effects onother adaptive and innate immune cellnumbers were much less than seenin asthma (31). The chronic airwayinflammation in (ex)smokers withCOPD thus appears to be resistant totreatment with ICS (32).
The latest version of the GlobalInitiative for Chronic Obstructive LungDisease (GOLD) strategic documentrecommends adding ICS to long-actingbronchodilator therapy in patients withCOPD with frequent exacerbations(30). However, this recommendation
is an oversimplification. First, COPDexacerbations are heterogeneous in natureand etiology, encompassing exacerbationsthat are eosinophil-predominant, requiringtreatment with systemic corticosteroids,and exacerbations that are caused bybacterial lower respiratory tract infections,needing treatment with antibiotics (33).Second, the use of ICS in patientswith COPD has been associated witha significantly increased risk of pneumonia,including severe pneumonia and fatalpneumonia (34, 35). Therefore, it seemslogical to tailor the add-on therapy inthe frequent COPD exacerbator to thepredominant underlying phenotypeof exacerbations and concomitantcomorbidities. In patients with frequentexacerbations due to bacterial respiratoryinfections and/or bronchiectasis, ICSshould be avoided—or stopped—andmaintenance treatment with macrolidessuch as azithromycin during winter seasonis an effective alternative (36). In contrast,adding ICS to single or dual bronchodilatortherapy will be beneficial in patients withfrequent eosinophil-predominant COPD
The ultimate goal is to develop a safeand effective antiinflammatory treatmentfor COPD that has a disease-modifyingeffect (i.e., preventing the accelerated declinein lung function and reducing mortality).The community of respiratory researchersand clinicians can learn a lot from therheumatology field, where several disease-modifying antirheumatic drugs have beendeveloped in the past 2 decades. Theclassical example of disease-modifyingantirheumatic drugs is biologics targetingtumor necrosis factor (TNF)-a, such asthe monoclonal antibodies infliximab,adalimumab, or golimumab and the solubleTNF-a receptor etanercept (37). Treatmentof patients with rheumatoid arthritis withanti–TNFa biologics—most frequentlyin combination with methotrexate—hasrevolutionized the management of thisdisease, not only providing symptomaticbenefit but also and most importantlypreventing the relentless destructionof joints. Because TNF-a is elevated insputum and bronchoalveolar lavage of
epithelium
neutrophil
muscarinic receptor
BACTERIAL
COLONISATION Macrolides
• azithromycin
• erythromycin
Bronchodilators
• LABA
• LAMA
Anti-inflammatory treatment
• ICS
• anti-IL17, IL-17R antibodies
• anti-TNF antibodies
Anti-B cell antibodies
• anti-CD20 (rituximab)
• anti-CD22 (epratuzumab)
• anti-BAFF (belimumab)
B-cell
HEV
macrophage
Th17 cellTh1 cell
dendritic cell
CD8+ cytotoxic T-cell
INFLAMMATION
LYMPHOID
FOLLICLES
TLR TLR
NLRP3
procaspase-1
caspase-1
K+
efflux
pro IL-1βpro IL-18
IL-1βIL-18
K
NF-kB
INFLAMMASOME
Inflammasome targeting
• NF-kB inhibitors
• caspase-1 inhibitors
• IL-1β , IL-18 antagonists
• IL-1RI , IL-18R antagonists
IL-1βIL-18
IL-1RI
IL-18R
ATP
p2x
7
β2-adrenergic receptor
smooth muscle cells
ASC
Figure 2. Overview of pathogenic pathways and possible therapeutic targets in patients with chronic obstructive pulmonary disease. Please see textfor discussion. ASC = apoptosis-associated speck-like protein containing a caspase activation and recruitment domain; BAFF = B-cell–activating factorbelonging to the tumor necrosis factor family; HEV = high endothelial venules; ICS = inhaled corticosteroids; LABA = long-acting b2-agonist; LAMA: long-actingmuscarinic antagonist; NLRP = nucleotide-binding oligomerization domain-like receptor, pyrin domain-containing; NF = nuclear factor; TLR = Toll-like receptor.
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patients with COPD and increases furtherduring exacerbations, TNF-a blockers havebeen investigated in placebo-controlledRCTs in COPD. Treatment of patients withmoderate to severe COPD with the anti–TNF-a monoclonal antibody infliximabfor 24 weeks did not improve symptoms,lung function, exercise capacity, or therate of exacerbations (38). In contrast,infliximab treatment in COPD wasassociated with numerical increases inmalignancies, especially lung cancer, andpneumonias, implicating major safetyconcerns. Two lessons are to be learnedfrom this landmark study. First, TNF-aappears to play an important role in tumorimmunosurveillance in the respiratorytract. Smokers with COPD and/oremphysema have indeed a significantincreased risk of lung cancer comparedwith smokers without airflow limitationand without emphysematous destructionof the lung parenchyma (39). Second, incontrast to the sterile inflammation of thejoints in rheumatoid arthritis, the airwaysand lungs of smokers, and especiallypatients with COPD, are colonized withpathogenic bacteria, which might not onlycause acute exacerbations of COPD and/orpneumonias but also amplify the chronicpulmonary inflammation in stable COPD(40–42). Several studies using non–culture-based techniques (e.g., 16S ribosomal RNAsequencing) have demonstrated that theairway microbiome is altered in patientswith COPD compared with healthycontrol subjects, including an increase inProteobacteria such as H. influenzae andP. aeruginosa (43). It is worthwhile toinvestigate the efficacy and safety oftocilizumab and other anti–IL-6 therapiesin COPD, because tocilizumab has provento be efficacious in other chronic immunediseases such as rheumatoid arthritisand because IL-6 levels are significantlyincreased in patients with COPD, bothlocally in the lungs and systemically in theblood (in a COPD subgroup with persistentsystemic inflammation).
Chronic treatment with the macrolidesazithromycin and erythromycin has beenshown to significantly prolong the timeto the first exacerbation and reduce theexacerbation rate in patients with moderateto very severe COPD and a history ofrepeated exacerbations (36, 44). Cautionis warranted because patients with COPDare elderly people with multimorbidities(including cardiovascular disease) and
polypharmacy (including drugs thatcause QT prolongation), increasing therisk of hearing decrements and cardiacarrhythmias (45, 46). An additionalconcern is the increase in macrolide-resistant bacteria (and mycobacteria)within the COPD and general population(29), implicating that the developmentof nonantibiotic macrolides withantiinflammatory, immunomodulatoryeffects is much needed. Importantly, bycomparing the clinical efficacy of thenew nonantibiotic macrolides withazithromycin in patients with COPDwith frequent exacerbations, we will getnovel insights into the relative contributionof the antibiotic effects versus theantiinflammatory effects of azithromycin.These pivotal studies will offer us theopportunity to unravel the pathogenicrole of bacteria such as H. influenzae inCOPD and thus to test the vicious circlehypothesis of chronic infection andinflammation in COPD (40–42).
In severe COPD, increased numbersof lymphoid follicles have been observedaround the small airways and in thelung parenchyma (47–49). Theseperibronchiolar and intrapulmonarylymphoid follicles mainly contain B cellsand plasma cells and are local factoriesproducing antibodies in the mucosa(including immunoglobulin A, which issecreted into the airway lumen as secretoryIgA after transport through bronchialepithelial cells via the polymericimmunoglobulin receptor). These locallyproduced antibodies might be directedagainst viral and bacterial microorganismsin the respiratory tract of patients withCOPD and thus be protective (50).However, the lymphoid follicles might alsoproduce autoantibodies against epithelialantigens, posttranslationally modifiedproteins, or degraded extracellular matrixproteins. Several autoantibodies have beendetected in serum of a subgroup of patientswith (severe) COPD (51–53), althoughthe presence of elastin autoantibodies inCOPD is controversial (54, 55). Oxidativestress, an essential component in thepathogenesis of COPD, can induceincreased levels of highly reactive carbonylsin the lung, resulting in the formation ofimmunogenic carbonyl adducts on self-proteins. These carbonyl-modified proteinshave been shown to promote autoantibodyproduction (56). Because lymphoidfollicles and autoantibodies are supposed
to play a pathogenic role in this severeCOPD phenotype with autoimmuneemphysema, anti–B-cell–directed therapiesusing monoclonal antibodies against CD20(e.g., rituximab), CD22 (epratuzumab),IL-6 (tocilizumab), or BAFF (belimumab)merit investigation in well-designed RCTs(57). However, long-term studies willbe required to demonstrate efficacy onexacerbations and disease progression,and close monitoring of infectious adverseevents is warranted.
An interesting new avenue in thetreatment of chronic airway inflammationin COPD is targeting the inflammasomes,which are intracellular multiproteincomplexes in myeloid and epithelial cellsthat facilitate the activation of the cysteineprotease caspase-1 (58). Active caspase-1subsequently cleaves the inactive pro–IL-1band pro–IL-18 proteins into bioactive IL-1band IL-18, two major proinflammatorycytokines recruiting additional innateimmune cells and skewing adaptive Thelper cell responses toward Th1 and/orTh17 (Figure 2). Interfering with theinflammasome/caspase-1/IL-1b/IL-18pathway can be accomplished at severallevels: by inhibiting nuclear factor-kB–dependent up-regulation of pro–IL-1band pro–IL-18, by preventing the assemblyof the inflammasome complex or theenzymatic activity of caspase-1, and byblocking the interaction between secretedIL-1b/IL-18 and their membrane receptors.Because IL-1a, a danger signal that isindependent from the inflammasome/caspase-1 axis, is also increased in sputumand lungs of patients with COPD (59),blocking the common IL-1RI (whichbinds both IL-1a and IL-1b) might bemore efficacious than specific caspase-1inhibitors or IL-1b blockers (e.g., the anti–IL-1b monoclonal antibody canakinumab).However, deficient mucosal inflammatoryresponses to microbes may predisposepatients with COPD to respiratory tractinfections and pneumonia.
Predictors of TherapeuticResponse versusTherapeutic Targets
Finally, it is important to bear in mindthat a predictor of therapeutic response doesnot implicate that this predictor per seis a therapeutic target. The discordancebetween a predictor of response and
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a therapeutic target is elegantly illustratedin the following examples. First, anincreased fraction of nitric oxide (NO)in the exhaled air of patients with asthma(either asthma-like symptoms such aschronic cough or a firm diagnosis ofasthma) is a predictor of a good responseto treatment with ICS (60). However,inhibiting inducible nitric oxide synthase(iNOS)—the enzyme responsible for theproduction of NO in the respiratorytract—did not improve lung function orsymptoms in patients with asthma (61).Second, the presence of neutrophilic
chronic airway inflammation is a predictorof therapeutic response to azithromycin(see above). However, specific antagonistsof mediators likely to be involved inthe chemotaxis and accumulation ofneutrophils into the airways have failed toshow clinical benefit in RCTs in COPD:antagonists of leukotriene B4, a CXCR2antagonist and a CXCL8 (formerly calledIL-8)-specific monoclonal antibody, wereineffective (32). Although we are eagerlyawaiting the results of clinical studiesinvestigating monoclonal antibodies againstIL-17, IL-17R, and IL-18 in COPD, the
current knowledge suggests that strategiesthat target the underlying causes of thepulmonary neutrophilia (e.g., smoking,oxidative stress, chronic infection, and soon) will be more successful than “cosmetic”strategies that merely decrease airwayneutrophilia without eradicating theunderlying drivers of neutrophilia. n
Author disclosures are available with the textof this article at www.atsjournals.org.
Acknowledgment: The author thanks LisaDupont for editorial assistance.
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S328 AnnalsATS Volume 11 Supplement 5| December 2014
