Severe asthma: Advances in current management and future ... · Asthma: Current status and future...

Asthma: Current status and future directions

Severe asthma: Advances in current management and futuretherapy

Peter J. Barnes, FMedSci, FRS London, United Kingdom

Abbreviations used

COPD: Chronic obstructive pulmonary disease

CRTH2: Chemoattractant homologous receptor expressed on TH2

cells

59-LO: 59-LipoxygenaseHDAC2: Histone deacetylase-2

ICS: Inhaled corticosteroid

LABA: Long-acting b2-agonist

LAMA: Long-acting muscarinic antagonist

LT: Leukotriene

MAPK: Mitogen-activated protein kinase

MIF: Migratory inhibitory factor

NF-kB: Nuclear factor kB

Nrf2: Nuclear factor erythroid 2–related factor 2

PDE: Phosphodiesterase

PG: Prostaglandin

PI3K: Phosphoinositide 3-kinase

PPAR: Peroxisome proliferator–activated receptor

Syk: Spleen tyrosine kinase

TSLP: Thymic stromal lymphopoietin

Effective treatment of severe asthma is a major unmet needbecause patients’ symptoms are not controlled on maximumtreatment with inhaled therapy. Asthma symptoms can bepoorly controlled because of poor adherence to controllertherapy, and this might be addressed by using combinationinhalers that contain a corticosteroid and long-acting b2-agonistas reliever therapy in addition to maintenance treatment. Newbronchodilators with a longer duration of action are indevelopment, and recent studies have demonstrated the benefitof a long-acting anticholinergic bronchodilator in addition tob2-agonists in patients with severe asthma. Anti-IgE therapy isbeneficial in selected patients with severe asthma. Several newblockers of specific mediators, including prostaglandin D2, IL-5,IL-9, and IL-13, are also in clinical trials and might benefitpatients with subtypes of severe asthma. Several broad-spectrum anti-inflammatory therapies that target neutrophilicinflammation are in clinical development for the treatment ofsevere asthma, but adverse effects after oral administrationmight necessitate inhaled delivery. Macrolides might benefitsome patients with infection by atypical bacteria, but recentresults are not encouraging, although there could be an effect inpatients with predominant neutrophilic asthma. Corticosteroidresistance is a major problem in patients with severe asthma,and several molecular mechanisms have been described thatmight lead to novel therapeutic approaches, including drugsthat could reverse this resistance, such as theophylline andnortriptyline. In selected patients with severe asthma, bronchialthermoplasty might be beneficial, but thus far, clinical studieshave not been encouraging. Finally, several subtypes of severeasthma are now recognized, and in the future, it will benecessary to find biomarkers that predict responses to specificforms of therapy. (J Allergy Clin Immunol 2012;129:48-59.)

Key words: Corticosteroids, bronchodilator, cytokine, chemokine,IgE, kinase, p38 mitogen-activated protein kinase, bronchial thermo-plasty, corticosteroid resistance, macrolide

Severe asthma is defined by a failure to achieve control withmaximum doses of inhaled therapies and represents one of themajor unmet therapeutic needs in asthma. Although current

From the National Heart and Lung Institute, Imperial College.

Disclosure of potential conflict of interest: P. J. Barnes receives research support from

GlaxoSmithKline, AstraZeneca, Novartis, Boehringer Ingelheim, and Pfizer.

Received for publication October 18, 2011; revised November 8, 2011; accepted for pub-

lication November 10, 2011.

Corresponding author: Peter J. Barnes, FMedSci, FRS, National Heart and Lung Insti-

tute, Imperial College School of Medicine, Dovehouse St, London SW3 6LY, United

Kingdom. E-mail: [email protected].

0091-6749/$36.00

� 2012 American Academy of Allergy, Asthma & Immunology

doi:10.1016/j.jaci.2011.11.006

48

management of asthma is highly effective, most patients’ symp-toms are well controlled if they take regular inhaled corticoste-roids (ICSs) with or without long-acting b2-agonists (LABAs)in combination inhalers. Yet despite the availability of highly ef-fective therapies, more than half of the patients with asthma in thereal world have disease that is apparently poorly controlled,largely because of poor adherence to controller therapy.1,2 In pa-tients with difficult-to-treat asthma, more than 80% show poor ad-herence with regular inhaled therapy.3 Even in the patients withthe most severe asthma treated with maintenance oral predniso-lone (steroid-dependent asthma), only about half of the patientstake the oral steroid based on plasma prednisolone assays. Thissuggests that poor adherence is a major factor contributing topoor control of asthma. In patients with refractory asthma withpersistent sputum eosinophilia despite prescription of high dosesof ICSs or maintenance oral steroids, treatment with high-dose in-tramuscular injection of triamcinolone results in disappearance ofsputum eosinophilia in the majority of patients.4 This suggeststhat poor compliance with inhaled and even oral corticosteroidsmight be a major factor contributing to difficult-to-treat asthmaand that poor compliance with controller therapy is an importantdeterminant of asthma severity.The reasons for poor compliance with regular therapy, espe-

cially in patients with severe asthma, are not well understood, butthe lack of immediate symptom relief, as seen with anti-inflammatory treatments, such as corticosteroids, is probablyimportant. Steps need to be taken to more accurately determineadherence to therapy, and strategies to overcome this problem

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http://dx.doi.org/10.1016/j.jaci.2011.11.006

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need to be devised. These findings also indicate that patientswith poorly controlled asthma might need additional anti-inflammatory therapy.This review discusses some of the currently available and

developing approaches to the management of severe or refractoryasthma. Several new classes of drugs are currently in developmentfor the treatment of severe asthma, but it has proved challengingto find effective and safe therapies.5 Although severe asthma com-prises only approximately 5% to 10% of all asthmatic patients, itaccounts for more than half of the health care spending on asthmabecause patients with severe asthma consume more expensivedrugs and are more likely to be hospitalized or require additionalmedical attention.

SMART STRATEGIESSeveral studies have shown that in patients with moderate-to-

severe asthma, there is an improvement in asthma control andsignificant reduction in severe exacerbations if a budesonide/formoterol combination inhaler is used as a reliever instead of ashort-acting b2-agonist, whereas maintenance therapy with bude-sonide/formoterol is administered twice daily as usual.6 Thisstrategy is now known as single inhaler maintenance and relievertherapy (SMART) and could presumably be used with any com-bination inhaler containing formoterol, irrespective of the cortico-steroid used. However, this strategy is not possible withsalmeterol or the once-daily b2-agonists, such as indacateroland vilanterol, all of which have cumulative side effects. The sci-entific rationale for SMART is now well understood because theICS used as rescue therapy has a rapid onset of its anti-inflammatory effect and prevents the build-up of inflammationthat precedes an acute exacerbation.7,8 The SMART strategy is ef-fective in patients with moderate and severe asthma, althoughstudies confined to severe asthma have not yet been conducted.6

This strategy might also be effective even when patients forgetdoses of their maintenance therapy and therefore addresses thekey issue of poor adherence with controller therapy discussedabove. Indeed, studies are now needed looking at inhaled formo-terol/steroid combination inhalers as rescue therapy, even in theabsence of the maintenance dose.9

NEW CORTICOSTEROIDSSeveral ICSs are currently available for clinical use, and all

have similar clinical efficacy, but there are differences in phar-macodynamic properties so that systemic exposure might differ.Because patients with severe asthma might require higher dosesof ICSs, there is an advantage in developing systemic corticoste-roids with fewer systemic side effects. Ciclesonide is a recentlydeveloped ICS and appears to have the least systemic effects andlocal side effects because the prodrug is activated in the lungs tothe active principle des-ciclesonide by esterases, whereas there islittle activation in the oropharynx.10 This suggests that high dosesof ciclesonide might be useful in the treatment of severe asthma.ICSs in pressurized metered-dose inhalers are now administeredwith hydrofluoroalkane 134a rather than chlorofluorocarbon asa propellant, and this results in smaller particle sizes, so that thedrugs are more likely to be deposited in the small airways.11 The-oretically, this should more effectively treat patients with severeasthma in whom there is inflammation of peripheral airwayswith evidence of small-airway inflammation.12 More studies are

needed on ICSs with hydrofluoroalkane 134a propellants in pa-tients with severe asthma.All currently available ICSs are absorbed from the lungs and

thus have the potential for systemic side effects. This has led to asearch for safer ICSs with reduced oral bioavailability, reducedabsorption from the lungs, or inactivation in the circulationbecause this would allow higher doses to be administered safelyin patients with severe asthma. ‘‘Dissociated’’ steroids attempt toseparate the side-effect mechanisms from the anti-inflammatorymechanisms. This is theoretically possible because side effectsare largely mediated through transactivation and the binding ofglucocorticoid receptors to DNA, whereas anti-inflammatoryeffects are largely mediated through transrepression of transcrip-tion factors through a nongenomic effect.13 Dissociated steroidsare designed to have a greater effect on transactivation than ontransrepression and thus might have a better therapeutic ratioandmight even be suitable for oral administration.14 Nonsteroidalselective glucocorticoid receptor activators, such as AL-438 andmapracorat, are in clinical development. However, some of theanti-inflammatory effects of corticosteroids might be due to trans-activation of anti-inflammatory genes, and therefore selectiveglucocorticoid receptor activators might not be as efficacious asexisting ICSs.15 Corticosteroids switch off inflammatory genesby recruiting the nuclear enzyme histone deacetylase-2(HDAC2) to the activated inflammatory gene initiation site sothat activators of this enzyme might also have anti-inflammatory effects or might enhance the anti-inflammatory ef-fects of corticosteroids.13

NEW BRONCHODILATORSBronchodilators play an important role in reducing symptoms

in patients with severe asthma, and currently, LABAs are thebronchodilators of choice, usually given in combination withICSs in a fixed-dose inhaler. Bronchodilators are essential in themanagement of asthma because they relieve and prevent bron-choconstriction. There have been several advances in the devel-opment of bronchodilators for the treatment of severe asthma.

Once-daily b2-agonistsb2-Agonists are the most effective bronchodilators because

they act as functional antagonists of airway smooth muscle con-traction, irrespective of the constricting stimulus. The LABAssalmeterol and formoterol have been a major advance in themanagement of severe asthma and are usually administeredthrough combination inhalers with corticosteroids. There havebeen concerns about the safety of LABAs, and there is convinc-ing evidence that LABAs used without a corticosteroid cover in-crease severe exacerbations and mortality. However, there is noclear evidence that LABAs pose any risk if combined with cor-ticosteroids and therefore should only be used in the form ofcombination inhalers.16,17 Several once-daily b2-agonists (‘‘ul-tra-LABAs’’) are in clinical studies, including indacaterol(already available for chronic obstructive pulmonary disease[COPD] in several countries), carmoterol, vilanterol, and oloda-terol.18 For asthmatic patients, these ultra-LABAs should onlybe available with a corticosteroid in a fixed combination. Cur-rently, fluticasone furoate/vilanterol and mometasone/indaca-terol are in clinical development for asthma as once-dailycombination inhalers.18


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Long-acting muscarinic antagonistsAntimuscarinic (anticholinergic) bronchodilators are the pre-

ferred first-line therapy in patients with COPD, but in patientswith asthma, they are less effective than b2-agonists because theyblock only the cholinergic component of bronchoconstriction,whereas b2-agonists reverse all bronchoconstrictors, includingthe direct effects of inflammatory mediators, such as histamine,leukotriene (LT) D4, and prostaglandin (PG) D2. Animal studieshave recently demonstrated an important role for cholinergicmechanisms in the late response to inhaled allergen in sensitizedguinea pigs because the long-acting muscarinic antagonist(LAMA) tiotropium bromide completely blocks the late responsein nonanesthetized animals.19 This response is also blocked bydrugs that block TRPA1, an activating ion channel on airway sen-sory nerves, suggesting that allergens release a mediator (thus farunidentified) that activates TRPA1, leading to cholinergic reflexbronchoconstriction. There is also increasing evidence that mus-carinic receptors can be activated by acetylcholine released fromnonneuronal cells, such as epithelial and inflammatory cells.20,21

Choline acetyltransferase can be induced in epithelial cells by in-flammatory mediators, such as TNF-a, suggesting that acetylcho-line synthesis might be increased in the airways of asthmaticpatients. In sensitized guinea pigs tiotropium inhibits eosinophilicinflammation in the airways and airway hyperresponsiveness,even in vagotomized animals, suggesting that tiotropium is block-ing the effects of nonneuronally released acetylcholine on musca-rinic M3 receptors and that tiotropium also blocks eosinophilicinflammatory mechanisms.22 Tiotropium also inhibits TH2 cyto-kine release in allergen-exposed sensitizedmice and that from hu-man PBMCs.23 It also reduces eosinophilic inflammation, mucingene expression, and airway remodeling in a murine model ofasthma, possibly through a direct effect on fibroblasts.24 Tio-tropium also inhibits neutrophilic inflammation and airway fibro-sis after repeated LPS challenge in guinea pigs.25 Theseexperimental studies suggest that tiotropium might have anti-inflammatory effects through antagonism of neuronally andextraneuronally released acetylcholine on M3 receptors on in-flammatory cells. There is also evidence that blocking M3 recep-tors with tiotropium inhibits acetylcholine-induced release ofneutrophil chemotactic factors (mainly LTB4) from human mac-rophages.26 These in vitro and experimental studies have pavedthe way to recent clinical studies of tiotropium in patients withasthma, particularly in those with severe disease. Recent studieshave shown that once-daily tiotropium provides useful additionalbronchodilatation when added to a LABA in some patients withsevere asthma. In one study approximately 30% of patients withsevere asthma showed a good additional response when tio-tropium was added.27 Addition of tiotropium significantly im-proves lung function in patients whose symptoms are notcontrolled by high doses of ICSs and LABAs, although there isno improvement in symptoms or health status.28 Another studyshowed that tiotropium was comparable with salmeterol in termsof bronchodilator response when added to an ICS in patients whoshow a good response to a short-acting anticholinergic.29 In asth-matic patients with the Arg16/Arg16 genotype of the b2-receptor,who have previously been reported to be less responsive to b2-ag-onists, once-daily tiotropium was no less effective than twice-daily salmeterol in patients whose symptoms are not controlledwith ICSs alone.30 These studies suggest that addition of aLAMA to existing therapy in patients with severe asthma not

controlled with ICSs and LABAs is beneficial and might be indi-cated, particularly in elderly patients with an element of fixed air-way obstruction, who have similarities to patients with COPD.There are several other LAMAs in clinical development for

COPD, including once-daily glycopyrrolate and GSK573719 andtwice-daily aclidinium bromide.31 There appears to be additivitybetween LABAs and LAMAs, suggesting that a triple combina-tion of a LABA plus a LAMA plus an ICS might be useful insome patients with severe asthma, although the development ofsuch inhalers might prove difficult technically and for regulatoryreasons.32 Several bifunctional molecules that have LABA andLAMA activity are also in development, but it might prove diffi-cult to balance the b-agonist and anticholinergic activities.33 Itwould be logistically easier to combine a bifunctional moleculethat has LABA and LAMA activity and an ICS in a combinationinhaler to provide triple activity.

Novel classes of bronchodilatorIn view of the recent concerns about the long-term safety of

LABAs in asthmatic patients, there has been a search foralternative classes of bronchodilator. Novel bronchodilatorshave proved difficult to develop, and new drugs, such as vasoac-tive intestinal peptide analogs and potassium-channel openers,have had side effects due to more potent vasodilator thanbronchodilator effects. A stable vasoactive intestinal peptideanalog, Ro 25-1553, has bronchodilator activity in asthmaticpatients but is less effective than inhaled formoterol.34 b2-Ago-nists and theophylline relax human airway smooth muscle by ac-tivating large-conductance Ca21-activated potassium channels,leading to a search for direct large-conductance Ca21-activatedpotassium channel activators, but although activating drugswere discovered, they have not been tested in clinical studies inasthma. Rho kinase inhibitors also have potential as bronchodila-tors but are likely to have significant toxicity. Recently, it has beenfound that agonists of bitter taste receptors (TAS2Rs), such as qui-nine, chloroquine, and saccharine, relax human airways in vitroby increasing local Ca21 release, resulting in the opening andhyperpolarization of airway smooth muscle cells.35 In murinemodels inhaled bitter tastants appear to be more effective than ab-agonist, although this species is not very responsive to b2-ago-nists. Theophylline relaxes human airway smooth muscle by in-hibiting phosphodiesterase (PDE) 3 in airway smooth musclecells, so that selective PDE3 inhibitors, such as cilostazol andmil-rinone, are potential bronchodilators. However, there has beenconcern that PDE3 inhibitors were associated with increased car-diovascular mortality in previous clinical trials. Combined PDE3/4 inhibitors are currently in development as inhaled therapy forasthma and COPD.36 PGE2 relaxes human airway smooth musclethrough EP4 receptors,37 suggesting that EP4-selective agonistsmight be useful bronchodilators and might avoid the coughing in-duced by PGE2 through EP3 receptors on sensory nerve endings.

ANTI-IgEOmalizumab is the only novel therapy that has specifically

been approved for the treatment of severe asthma. Omalizumabis an mAb that binds the Fc portion of IgE and thus preventsactivating its high-affinity IgE receptor (FcεRI) on mast cells,basophils, and dendritic cells, as well as a low-affinity receptor

FIG 1. PGD2 might play a role in severe asthma. It is synthesized mainly in

mast cells by PDGD synthase (PGDS) and acts on DP1 receptors on vessels

to mediate vasodilatation and on dendritic cells to enhance their activation

through DP2 receptors (also known as CRTH2) to attract TH2 lymphocytes

and eosinophils and on thromboxane (TP) receptors to cause bronchocon-

striction. DP2 (CRTH2) antagonists are now in a clinical trial in patients with

severe asthma. Antagonists of DP1 and receptors and inhibitors of PGDS

are now in clinical development for asthma therapy. Adapted from Barnes.5



BARNES 51

(FcεRII) expressed on several immune and inflammatory cells,including macrophages, eosinophils, and T and B lymphocytes.Numerous clinical trials have demonstrated the clinical efficacyof omalizumab in reducing maintenance doses of oral cortico-steroids and ICSs and in reducing exacerbations in patients(including children) with severe asthma.38-40 In a large study ofpatients with severe asthma whose symptoms are not controlledwith high doses of ICSs and LABAs, omalizumab significantlyreduced exacerbations (by 25%) and improved symptoms andasthma-related quality-of-life scores.39 Only a proportion of al-lergic asthmatic patients with the target total serum IgE concen-tration of 70 to 300 IU/mL show a good response, and becauseof the high cost, a trial of therapy over 3 to 4 months is oftenrecommended to identify good responders. Unfortunately, de-spite extensive analyses, no clinically measurable biomarkershave been found to predict a good response. Patients with non-atopic (intrinsic) asthma are currently excluded, but there is ev-idence for local IgE production in the airways of at least someof these patients,41 and therefore future studies should investi-gate this group of patients who often have difficult-to-controlasthma. Similarly, there are patients with severe uncontrolledasthma with total IgE levels of greater than 300 IU/mL whoare currently excluded because it is not feasible to give enoughantibody to effectively block IgE. In the future, antibodies witha higher affinity for IgE might be developed so that it could bepossible to treat patients with very high total IgE levels. AnmAb (lumiliximab) directed against FcεRII (CD23) reduces to-tal IgE levels, probably by reducing synthesis by B lympho-cytes, but has little clinical benefit, even in patients with mildasthma, and therefore is no longer in clinical development.42

TARGETING INFLAMMATORY MEDIATORSMore than 100 mediators are involved in the complex inflam-

mation of asthma, making it unlikely that blocking the synthesisor receptor for a single mediator could be very effective. ICSs arehighly effective in suppressing the synthesis of multiple inflam-matory mediators, but in patients with severe asthma, they appearto be less effective, making it possible that adding a mediatorantagonist to high doses of ICSs might be beneficial. In addition,the inflammation seen in some patients with severe asthma has adifferent pattern, with a predominance of neutrophils, suggestingthat targeting mediators of neutrophilic inflammation might beeffective in these patients.43

Lipid mediator blockadeThe only mediator antagonists currently used in asthma

therapy are antileukotrienes, which block cysteinyl leukotrienereceptors, but these drugs are much less effective than ICSs andhave little place as add-on therapy in patients with severeasthma.44 LTB4 is a chemoattractant of neutrophils, mast cells,and T cells, including effector CD81 memory T cells, and itslevels are increased in patients with severe asthma.45 AnLTB4 receptor (BLT1) antagonist had no effect in patientswith mild asthma46 but has not been tested in patients withmore severe disease, in whom it would be more likely to be ef-fective. A low-affinity BLT2 receptor is expressed on severalcell types, including T cells and mast cells, and when inhibitedby oligonucleotides, there is a reduction in allergic inflamma-tion in a murine model.47 BLT2 receptors are upregulated on

mast cells after allergen challenge and mediate the synthesisof TH2 cytokines.48 To target both BLT1 and BLT2, LTB4 syn-thesis can be reduced by an inhibitor of LTA4 hydrolase, andsuch an approach is effective in a murine model of asthma.49

Phospholipase A2 inhibits the generation of all lipid mediators(prostaglandins, leukotrienes, and platelet-activating factor) frommembrane phospholipids and therefore theoretically should be ef-fective in patients with severe asthma, although there is uncer-tainty about whether to block the secretory or cytosolicisoforms of phospholipase A2, and it has been difficult to discoversafe and selective inhibitors.50

59-Lipoxygenase (59-LO) works through 59-LO–activatingprotein, and several novel 59-LO and 59-LO–activating proteininhibitors are currently in clinical development. These drugscould bemore effective than BLT1 antagonists because they blockproduction of additional mediators, such as 5-HETE and 5-oxo-ETE, which acts through a specific OXE receptor.51 5-Oxo-ETEis generated by oxidative stress and therefore is likely to be gen-erated in patients with severe asthma. It is a potent attractant ofeosinophils but also attracts neutrophils and T cells.PGD2 is released from mast cells, TH2 cells, and dendritic

cells and activates DP2 receptors, also known as chemoattractanthomologous receptor expressed on TH2 cells (CRTH2), whichmediate chemotaxis of TH2 cells and eosinophils (Fig 1).5,52

There is increased expression of PGD2 in patients with severeasthma.53 Several CRTH2 antagonists are now in clinical devel-opment for asthma, including AMG-853, OC000459, andMK-7246, which have shown early clinical efficacy as oral treat-ments for asthma and rhinitis. A study of OC00049 in steroid-naive asthmatic patients showed no improvement in lungfunction but a small reduction in symptoms and no significantreduction in sputum eosinophil numbers compared with thosevalues after placebo.54 PGD2 also activates DP1 receptors, whichmediate vasodilatation and enhance TH2 cell polarization bydendritic cells, so that a dual DP1/DP2 antagonist might bemore effective, whereas an inhibitor of PGD synthase wouldblock PGD2 synthesis and also prevent the bronchoconstrictoreffects of PGD2 that are mediated through thromboxane recep-tors on airway smooth muscle.


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Cytokine blockadeCytokines play a key role in orchestrating chronic inflamma-

tion and remodeling airway structure and therefore have becomeimportant targets for blockade in asthmatic patients, particularlypatients with severe disease whose symptoms are not controlledwith high doses of ICSs.55 More than 50 cytokines have been im-plicated in asthma, and several have already been targeted in clin-ical studies, often with disappointing results.56 There is a greatredundancy of cytokines, and therefore it might be difficult to in-hibit an inflammatory process effectively with a selective blocker.Another problem is the high cost of blocking mAbs, and thereforethese drugs are likely to be cost-effective only in patients with se-vere disease. It is possible that production costs might be reducedby the development of higher-affinity antibodies or the use offragments, such as domain antibodies, that are cheaper toproduce.Another problem is that there has been a major focus on TH2

cytokines in the belief that TH2 cells drive allergic inflamma-tion.57 Corticosteroids are very effective in suppressing TH2cell–driven inflammation, at least in part because they are verypotent inhibitors of the TH2 regulating transcription factorGATA3.58 Animal models of asthma have also been developedthat highlight TH2 cell–driven inflammation, and these modelsmight be inappropriate for the development of treatments for se-vere asthma.Because different immune mechanisms are likely operate in

many patients with severe asthma, it might be necessary to targetdifferent sets of cytokines, such as those involving TH1 andTH17 cells. TH17 cells have been implicated in patients with se-vere asthma, particularly those patients with a predominantlyneutrophilic pattern of inflammation.59 Interestingly, TH17 cellsappear to be corticosteroid resistant and might therefore contrib-ute to the corticosteroid resistance seen in patients with severeasthma.60

Inhibiting TH2 cytokinesInhibition of IL-4 by using inhaled soluble receptors proved to

be disappointing, but there is continued interest in blocking IL-13, a related cytokine that regulates IgE formation, particularlyin patients with severe asthma. IL-13 can also induce cortico-steroid resistance and therefore appears to be an appropriatetarget for patients with severe asthma.61,62 Pitrakinra is a mu-tated form of IL-4 that blocks IL-4 receptor a, the common re-ceptor for IL-4 and IL-13, and significantly reduces the lateresponse to inhaled allergen in patients with mild asthmawhen administered subcutaneously or by means of nebuliza-tion,63 and larger clinical trials are currently in progress withthis protein. Several IL-13 and IL-4 receptor a blocking anti-bodies are also in clinical development, but thus far, clinicalstudies in patients with severe asthma have been disappointing.A blocking mAb to IL-13, lebrikizumab, has been studied inasthmatic patients whose symptoms are not controlled withhigh doses of ICSs and showed a small increase in FEV1 (ap-proximately 5%) compared with placebo after 12 weeks butno significant effect at 24 weeks.64 There are no significant im-provements in symptoms or asthma-related health status and noreduction in exacerbations. Interestingly, increased concentra-tions of the plasma biomarker periostin, which was discoveredby means of proteomic analysis of IL-13–stimulated epithelialcells, showed a slightly better response (approximately 8%)

than low concentrations, suggesting that it can be used as a bio-marker to predict greater responses. An mAb targeting IL-4 re-ceptor a (AMG317), which therefore blocks the effects of IL-4and IL-13, has been ineffective in controlling asthma symptomsor lung function in 3 different doses over a 12-week period inpatients with mild asthma.65

One question about the poor efficacy of anti–IL-13 strategiesmight bewhether the dose is sufficient to block endogenous IL-13in the airways. In a recent study a blocking anti–IL-13 mAbprofoundly suppressed IL-13 in nasal secretions after localallergen challenge, yet there was no significant reduction ineosinophil numbers or nasal symptoms.66 IL-4 and IL-13 signalthrough the transcription factor signal transducer and activatorof transcription 6, and small-molecule inhibitors, such asAS1517499, have now been developed that are active in a murinemodel of asthma but have yet to be developed clinically.67

IL-5 is of critical importance for eosinophilic inflammation,and a blocking antibody to IL-5 (mepolizumab) depletes eosin-ophils from the circulation and sputum of asthmatic patients butdisappointingly has no effect on the response to inhaled allergen,airway hyperresponsiveness, symptoms, lung function, or exac-erbation frequency in asthmatic patients.68,69 However, more re-cent studies show that mepolizumab reduces exacerbations inhighly selected patients who have persistent sputum eosinophiliadespite high doses of ICSs, although there is no improvement insymptoms, lung function, or airway hyperresponsiveness.70,71

Another IL-5 blocking antibody, reslizumab, failed to improveasthma control over 12 weeks in patients with sputum eosino-philia despite high doses of ICSs, but there was some reductionin symptoms and sputum eosinophils.72 An antibody against theIL-5 receptor a (benralizumab, MEDI-563) might more effec-tively deplete airway eosinophils than blocking IL-5 itselfthrough antibody-dependent cytotoxicity of eosinophils and iscurrently being studied in clinical trials.73 Inhaled antisenseoligonucleotides that block the common b chain of IL-5 andGM-CSF receptors together with the chemokine receptor CCR3(TPI ASM8) have a small effect in reducing allergen responsesand airway inflammation.74 Overall, blocking IL-5, although ef-fective in reducing eosinophilic inflammation, has been disap-pointing, although it might be effective in highly selectedpatients, as well as in patients with other hypereosinophilic dis-eases, such as Churg-Strauss syndrome and eosinophilicesophagitis.75,76

Another TH2 cytokine that is currently being targeted is IL-9,which plays a role in mast cell proliferation, although there isrecent evidence that it is produced particularly by a subset ofCD41 T cells designated TH9 cells.77 Clinical studies havebeen encouraged by animal studies showing that inhibition ofIL-9 leads to reduced allergic inflammation and mucus hyperse-cretion, and a blocking IL-9 antibody (MEDI-528) has beenshown to be safe after weekly subcutaneous injections, with atrend toward reduction in exercise-induced asthma, which is me-diated through mast cell activation.78 Larger clinical trials arenow in progress.There has been considerable interest in thymic stromal

lymphopoietin (TSLP), an IL-7–related cytokine that is secretedby airway epithelial cells, because it instructs dendritic cells tosecrete chemokines that attract TH2 cells into the airways and po-tentiates the activation of these cells.79 TSLP expression by air-way epithelial cells is increased in a subset of patients withsevere asthma treated with high doses of ICSs, suggesting that



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this might be a good target, especially because it acts as an up-stream cytokine.80 Several pharmaceutical companies are devel-oping antibodies to TSLP and its receptor, as well as to OX40and OX40 ligand, which act as costimulatory molecules toTSLP, although bronchial OX40/OX40 ligand expression is notincreased in patients with severe asthma compared with thatseen in patients with mild asthma.81

Other cytokinesAnother cytokine targeted in asthmatic patients is TNF-a,

which might play a significant role in those with severe asthma.Several uncontrolled or small studies suggested that anti-TNFtherapies (TNF blocking antibodies infliximab or soluble receptoretanercept) might be useful in reducing symptoms, exacerbations,and airway hyperresponsiveness in patients with severeasthma,82,83 but a recent large multicenter trial with the human-ized antibody golimumab showed no beneficial effect on lungfunction, symptoms, or exacerbations, and there were increasedreports of pneumonia and cancer.84 A study of etanercept over4 weeks in patients with moderate-to-severe asthma showed noclinical efficacy, but there were no safety problems.85

Several other cytokine blockers are currently being targeted inasthmatic patients, including IL-17, IL-25, IL-33, GM-CSF, andstem cell factor, but thus far, no clinical studies in patients withsevere asthma have been reported.56

Chemokine receptor antagonistsChemokines are small cytokines that attract inflammatory

cells, includingmast cells, eosinophils, and TH2 cells, into the air-ways and are therefore appropriate targets for therapy, particu-larly because they signal through G protein–coupled receptorsfor which small-molecule antagonists can be developed.86 Themajor focus of interest in asthmatic patients has been the chemo-kine receptor CCR3, which is predominantly expressed on eosin-ophils and mediates the chemotactic response to CXCL11(eotaxin), which is secreted in asthma. CCR3 is also expressedon mast cells and some TH2 cells. Several small-molecule inhib-itors of CCR3 have been in clinical development, but their effectsin asthmatic patients have not yet been reported because they haveusually been discontinued because of toxicology problems. An in-haled antisense oligonucleotide that targets CCR3 has some effectin reducing sputum eosinophils, but results are difficult to inter-pret because IL-5 and GM-CSF b chain antisense were coadmi-nistered.87 Other chemokine receptors that are targeted forasthma therapy are CCR2 on monocytes and T cells and CCR4,CCR8, and CXCR4 on TH2 cells. A defucosylated antibody toCCR4 (mogamulizumab, also known as KW-0761 and AMG-761) results in prolonged cytotoxic effects on TH2 cells, markedand prolonged depletion of TH2 cells, and reduced lung inflamma-tion in animal models. This antibody is now in early clinical trialsfor asthma and adult T-cell leukemia-lymphoma.88 CXCR2 is ex-pressed on neutrophils and monocytes and might be involved inthe recruitment of neutrophils into the airways of patients with se-vere (neutrophilic) asthma. Several small-molecule inhibitors ofCXCR2 are now in clinical development.89 An oral CXCR1/CXCR2 antagonist, navarixin (SCH-527123), is effective inblocking ozone-induced sputum neutrophilia in healthy sub-jects90 and is currently in clinical trials in patients with severeasthma.

BROAD-SPECTRUM ANTI-INFLAMMATORY

TREATMENTSThe fact that the symptoms of patients with severe asthma

might not be controlled by high doses of ICSs plus LABAs andsometimes even oral corticosteroids has prompted a search foralternative anti-inflammatory therapies that can be added toexisting therapies to provide additional control. In addition,inflammation in some patients with severe asthma is predomi-nantly neutrophilic so that inhibitors of neutrophilic inflammationare needed, and corticosteroids are poorly effective againstneutrophilic inflammation. Several approaches to treating neu-trophilic inflammation might be applicable to the treatment ofsevere asthma. Although several classes of broad-spectrumnoncorticosteroid anti-inflammatory treatments have been indevelopment, there have usually been problems with side effectswhen the drugs are administered orally, and this has had limitedclinical development. This suggests that it might be necessary todevelop potent topically active anti-inflammatory treatments thatavoid systemic exposure, but thus far, this has proved to be amajor challenge.

PDE4 inhibitorsThe most advanced of the anti-inflammatory therapies are

PDE4 inhibitors, which have a wide spectrum of anti-inflammatory effects that are relevant to severe asthma, inhibitingT cells, eosinophils, neutrophils, mast cells, airway smoothmuscle, epithelial cells, and nerves and are highly effective inanimal models of asthma.91 PDE4 inhibitors are effective againstneutrophilic inflammation, making them an attractive potentialtherapy for severe asthma when there is neutrophilic inflamma-tion. An oral PDE4 inhibitor, roflumilast, has an inhibitory effecton allergen-induced responses in patients with mild asthma andalso reduces symptoms and lung function similar to a low doseof ICS.92 Roflumilast is currently licensed for use in patientswith severe COPD, and therefore there has been increased interestin its potential for the treatment of severe asthma. However, a ma-jor limitation to this class of drug is the mechanism-based side-ef-fect profile, including nausea, headaches, and diarrhea, which isdose limiting. On the basis of animal models, the anti-inflammatory effects appear to be mediated by inhibition ofPDE4B, whereas nausea and vomiting are mediated throughPDE4D inhibition, suggesting that PDE4B-selective inhibitorsmight be better tolerated.93 Another approach is to deliverPDE4 inhibitors by means of inhalation, but thus far, these drugshave had no efficacy. Inhaled PDE3/4 inhibitors are also in devel-opment and might have the advantage of bronchodilatationthrough PDE3 inhibition.36

Kinase inhibitorsKinases play a key role in regulating the expression of

inflammatory genes in asthmatic patients and might amplifyinflammation in patients with severe asthma.94 There are now sev-eral kinase inhibitors that might be useful in the treatment of se-vere asthma (Fig 2). The transcription factor nuclear factor kB(NF-kB) regulates many of the inflammatory genes that are ab-normally expressed in asthmatic patients and is activated in asth-matic airways. Small-molecule inhibitors of the key enzymeIKK2/IKKb (inhibitor of kB kinase) block inflammation inducedby NF-kB activation and are now in preclinical testing.95

FIG 2. Inhibition of proinflammatory kinase pathways for severe asthma.

Several kinases activate the expression ofmultiple inflammatory genes and

might therefore amplify the inflammation in asthmatic patients, leading to

more severe disease. Selective inhibitors have been developed for several

kinases, including spleen tyrosine kinase (SYK), which activates several

signaling pathways, including phospholipase Cg (PLCg); inhibitor of NF-

kB kinase (IKK2), which activates NF-kB; p38 MAPK, which activates

MAPK-activated protein kinase 2 (MAPKAPK2); Jun kinase (JNK), which ac-

tivates activator protein 1 (AP-1); and PI3K, which activates Akt. Selective

inhibitors have now been developed for all of these enzyme targets.

FIG 3. Inhibition of mast cells in asthmatic patients. Mast cell activation can

be inhibited by blocking IgE binding to FcεRI; by inhibiting c-Kit, which is

activated by stem cell factor (SCF); or by inhibiting spleen tyrosine kinase

(SYK). Mast cell stabilizers, such as cromones and furosemide, might

work through specific ion channels or G protein–coupled receptors for

which novel modulators can be developed. Adapted from Barnes.5


JANUARY 2012

54 BARNES

p38 mitogen-activated protein kinase (MAPK) activatessimilar inflammatory genes to NF-kB, is activated in cells frompatients with severe asthma,96 and has been linked to corticoste-roid resistance.97 A p38 MAPK inhibitor appears to improve cor-ticosteroid responsiveness in cells from patients with severeasthma.98 p38 MAPK also plays a key role in activation ofGATA3, a transcription factor that regulates TH2 cell differentia-tion and expression of TH2 cytokines.99 Corticosteroids blockGATA3 activation and are mimicked by p38 MAPK inhibitors.58

An antisense that blocks p38 MAPK demonstrated efficacy in amurine asthma model.100 Several small-molecule p38 inhibitorsare now in clinical development for the treatment of inflammatorydiseases, but side effects after systemic administration haveproved to be a major problem.101

Phosphoinositide 3-kinase (PI3K) also regulates inflammationand has several isoforms, but nonselective inhibitors are likely tobe toxic.102 The isoenzyme PI3Kg is important in chemotactic re-sponses, and selective inhibitors are in development, whereasPI3Kd activation results in reduced corticosteroid responsivenessthrough reduced HDAC2 activity, so that PI3Kd inhibitors mightpotentially reverse corticosteroid resistance in patients with se-vere asthma.103 Theophylline is a selective inhibitor of PI3Kd,and theophylline derivatives that lack PDE inhibition or selectivePI3Kd inhibitors might therefore be of therapeutic value.A general concern about novel kinase inhibitors is that they mighthave side effects because they target mechanisms that are found inmany cell types. Therefore it might be necessary to develop in-haled formulations for use in asthmatic patients in the future, asproved necessary for corticosteroids.Spleen tyrosine kinase (Syk) is involved in activation of mast

cells and other immune cells, and several small-molecule Sykkinase inhibitors are in development, particularly for patients withsevere asthma.104 An antisense inhibitor of Syk kinase is effectivein an animalmodel of asthma,105 and the small-molecule inhibitorR112 administered nasally reduces nasal symptoms in patientswith hay fever.106 More potent inhibitors, such as R343 andBay 61-3606, are in development for inhalation in asthmatic

patients. Because Syk is widely distributed in immune and neuro-nal cells, there are concerns about side effects. As with otherkinase inhibitors, there can be side effects with systemic admin-istration, and therefore inhalation might be preferred.

Peroxisome proliferator–activated receptor gagonists

Peroxisome proliferator–activated receptor (PPAR) g agonistshave a wide spectrum of anti-inflammatory effects, includinginhibitory effects on macrophages and T cells and neutrophilicinflammation, and polymorphisms of the PPARg gene have beenlinked to increased risk of asthma.107 The PPARg agonist rosigli-tazone produced a small improvement in lung function in smok-ing asthmatic patients in whom ICSs were ineffective108 and amodest (15%) reduction in late response to inhaled allergen in pa-tients with mild asthma.109 This suggests that PPARg agonists,such as thiazolidinediones, have little therapeutic potential inasthma therapy.

MAST CELL INHIBITORSMast cell activation is important as a driving mechanism in

some patients with severe asthma.53 There are several approachesto inhibitingmast cell activation (Fig 3),5 and anti-IgE has alreadybeen shown to be of value in the treatment of some patients withsevere asthma. Stem cell factor is a key regulator of mast cell sur-vival in the airways and acts through the receptor c-Kit on mastcells.110 Plasma concentrations of stem cell factor are increasedin patients with severe asthma.111 Blockade of stem cell factoror c-Kit is effective in animal models of asthma, suggesting thatthis pathway might be a good target for new asthma therapies.Masitinib is a potent tyrosine kinase inhibitor that blocks c-Kit(as well as platelet-derived growth factor receptors) and providessome symptomatic benefit in patients with severe asthma.112

More selective c-Kit inhibitors are in development.Cromones (cromolyn sodium and nedocromil sodium) inhibit

the activation of human mucosal mast cells and are very effectiveagainst allergen and other indirect challenges that involve mastcell activation.113 The effects of cromones are closely mimicked

FIG 4. Corticosteroid resistance in some patients with severe asthma is due to a reduction in HDAC2 activity

and expression as a result of oxidative stress through activation of PI3Kd. This can be reversed by

antioxidants, including Nrf2 activators, theophylline, nortriptyline, and selective PI3Kd inhibitors. Macro-

lides also reverse corticosteroid resistance by acting further down the pathway. In the future, selective

HDAC2 activators might be developed.



BARNES 55

by the diuretic furosemide, suggesting that they might act throughion channels. However, the molecular target for cromones wasnever identified, although recent studies suggest that an orphanG protein–coupled receptor called GPR35 might be a target.114

THE PROBLEM OF CORTICOSTEROID RESISTANCEResistance to the anti-inflammatory effects of corticosteroids

might be an important factor in determining asthma severity.Several molecular mechanisms have now been described toaccount for corticosteroid resistance in asthmatic patients, in-cluding activation of p38 MAPK activity (as described above),increased expression of an alternatively spliced variant of theglucocorticoid receptor GRb, increased production of macro-phage migratory inhibitory factor (MIF), and reduced expressionof HDAC2.115 This suggests that there might be therapies thatcould potentially reverse corticosteroid resistance and that theremight be different phenotypes of corticosteroid resistance inasthma that could require different therapeutic approaches. p38MAPK inhibitors have been shown to increase the anti-inflammatory responses to corticosteroids in PBMCs from pa-tients with severe asthma,98 and as discussed above, p38 MAPKinhibitors are in clinical development for the treatment of severeasthma. MIF is reported to be increased in patients with severeasthma and block the anti-inflammatory effects of corticoste-roids,116 but the molecular mechanisms are poorly understood,and it has been difficult to find drugs that block its actions.117

MIF can signal and cause corticosteroid resistance through the ac-tivation of p38 MAPK.118

HDAC2 activationThere is increasing evidence that corticosteroid resistance in

patients with COPD is due to a reduction in HDAC2 activity andexpression as a result of oxidative and nitrative stress.119 This re-sults in increased acetylation of the glucocorticoid receptor,

which prevents it from inhibiting NF-kB–driven inflammation.120

There is evidence that a similar mechanism might underlie corti-costeroid resistance in patients with severe asthma, in whom thereis increased oxidative stress from endogenously generated oxi-dants.121,122 A novel therapeutic strategy is reversal of this corti-costeroid resistance by increasing the expression and activity ofHDAC2, and this can be achieved in several ways (Fig 4).Low doses of oral theophylline increase HDAC2 expression in

alveolar macrophages from patients with COPD and therebyrestore steroid responsiveness.123,124 It has previously beenshown that addition of low-dose theophylline to moderate dosesof ICSs is more effective in patients with severe asthma than in-creasing the dose of ICS to the maximum tolerated dose125 andthat withdrawal of low-dose theophylline causes a loss of asthmacontrol in patients with severe asthma.126 In smoking asthmaticpatients who become refractory to corticosteroids, low-dosetheophylline is effective when added to a dose of ICS, which isineffective alone.127 The molecular mechanism of action oftheophylline in increasing HDAC2 levels is independent ofPDE inhibition and appears to be mediated by inhibitionof oxidant-activated PI3Kd.103,128 The tricyclic antidepressantnortriptyline also reverses corticosteroid resistance by inhibitingPI3Kd and therefore might have clinical benefit as an add-on ther-apy, although clinical trials have not yet been done in patientswith severe asthma.129 Selective PI3Kd inhibitors might be ofpotential value in patients with severe asthma in combinationwith ICSs. Selective PI3Kd inhibitors are now in clinical develop-ment for the treatment of B-cell leukemia but might also be usefulin patients with severe asthma, especially if administered bymeans of inhalation to avoid any hematologic side effects.

AntioxidantsOxidative stress is increased in patients with severe asthma,130

particularly during exacerbations, and reactive oxygen speciesare likely to amplify inflammation and contribute to its


JANUARY 2012

56 BARNES

pathophysiology. Oxidative stress also reduces steroid respon-siveness through a reduction in HDAC2 activity and expression.This suggests that antioxidants might reverse corticosteroid resis-tance and also reduce inflammation. Unfortunately, currentlyavailable antioxidants based on glutathione are relatively weakand are inactivated by oxidative stress, and therefore new andmore potent and stable antioxidants are needed, such as superox-ide dismutase mimics and NADPH oxidase inhibitors.131 Thetranscription factor nuclear factor erythroid 2–related factor 2(Nrf2) plays a key role in the regulation of endogenous antioxi-dant genes and might be dysfunctional in patients with severeasthma. Several Nrf2 activators, such as sulforaphane (whichoccurs naturally in broccoli) and the synthetic triterpenoid 1-(2-cyano-3-,12-dioxooleana-1,9-dien-28-oyl)imidazole-methyl es-ter, have now been identified,132 and Nrf2 activators are now inclinical development.

MACROLIDESThere is evidence that some patients with severe asthma are

chronically infected with atypical bacteria, such as Mycoplasmapneumoniae and Chlamydia pneumoniae.133 In patients with in-fection confirmed by means of PCR and culture, there was a sig-nificant improvement in FEV1 after a 6-week course ofclarythromycin.134 However, in a larger trial of patients withpoorly controlled asthma, treatment with clarithromycin over a16-week period did not produce any clinically meaningful im-provement in asthma control, even in the patients who had posi-tive PCR results for atypical bacteria, although there was asignificant reduction in airway hyperresponsiveness.135 It haslong been recognized that macrolides have anti-inflammatory ef-fects that might be independent of their antibiotic effects.136Mac-rolides appear to inhibit inflammation by inhibiting NF-kB andother transcription factors, but the precise molecular mechanismshave not yet been determined. In patients with severe neutrophilicasthma, a course of azithromycin significantly reduced sputumneutrophil numbers and CXCL8 concentrations, with some im-provement in symptoms.137 This suggests that it might be worthusing a therapeutic trial of macrolide antibiotics in patients withsevere asthma who have predominantly neutrophilic inflamma-tion. A nonantibiotic macrolide (EM-703) reverses corticosteroidresistance caused by oxidative stress by increasing HDAC2 activ-ity.138 Several nonantibiotic macrolides are now in developmentas anti-inflammatory therapies.139

BRONCHIAL THERMOPLASTYBronchial thermoplasty delivers controlled thermal energy to

the bronchial wall to selectively reduce the amount of airwaysmooth muscle and has been studied in patients with severeasthma. It is usually administered as 3 outpatient bronchoscopicprocedures separated by 3 weeks. In a large controlled trial ofalmost 200 patients with severe asthma, bronchial thermoplastycompared with a sham procedure produced a small improvementin asthma-specific quality-of-life scores (although this was farless than the minimal clinically significant difference for this test)and a small reduction in exacerbations after treatment.140 How-ever, significantly more patients were hospitalized, and thereforeit is uncertain whether the small clinical benefit is justifiable. Inanother study asthma control was improved compared with thatseen in a control group in patients taking ICSs in whom long-

acting b2-agonists were withdrawn,141 suggesting that it wouldprovide no greater benefit than a bronchodilator. The safety ofthe procedure has been followed for up to 5 years with no lossof lung function, suggesting that there are no structural changesas a consequence of the therapy.142 It is still unclear how muchbenefit this procedure provides in patients with severe asthma,and the clinical outcomes show little change and might noteven be apparent when patients are treated with long-acting bron-chodilators. It is possible that this procedure is indicated in care-fully selected patients in whom airway smooth musclehypertrophy is predominant, as evidenced by pronounced airwayhyperresponsiveness. The mechanism of action of bronchial ther-moplasty has been determined from studies in normal dogs, and itis uncertain how the procedure affects the airways of asthmaticpatients or whether it leads to reduced inflammation by reducingairway smooth muscle cell secretion of inflammatory mediatorsin the airways of asthmatic patients.

FUTURE DIRECTIONSIt is now becoming clear that there are several distinct

phenotypes of severe asthma and that these might requiredifferent therapeutic approaches. For example, patients whosesymptoms were not controlled on maximal inhaled therapies thathave high sputum eosinophilia and frequent exacerbations mightbenefit from anti–IL-5 therapy with mepolizumab or reslizumab.By contrast, neutrophilic asthma might respond to anti-inflammatory therapies that target neutrophilic inflammation,including PDE4 inhibitors, p38 MAPK inhibitors, CXCR2antagonists, or macrolides. Corticosteroid resistance is likely tobe an importantmechanism contributing to poor treatment controlin patients with severe asthma and might respond to therapies thattarget the molecular mechanisms of corticosteroid resistance,such as p38 MAPK inhibitors in some patients, or treatments thatincrease HDAC2 levels, such as theophylline, nortriptyline, andPI3Kd inhibitors among others. Analysis of large datasets ofadults and children with severe asthma is now beginning torecognize distinct phenotypes.143,144 It will be important to iden-tify biomarkers that predict response to identify therapeutic sub-phenotypes of asthma, and this area requires more research so thattherapy can be personalized, particularly for therapies that targetspecific mediators or mechanisms, because only a small propor-tion of patients with severe asthma are likely to respondadequately.

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