what is new in the management of childhood asthma?

Indian Journal of Pediatrics, Volume 75—August, 2008 845

Correspondence and Reprint requests : Dr. Varinder Singh,Professor, Department of Pediatrics, Lady Hardinge Medical Collegeand Kalawati S Children’s Hospital, New Delhi 110001. India.Mobile : 9899666510

Symposium on Advances in Therapy

What is New in the Management of Childhood Asthma?

Varinder Singh

Department of Pediatrics, Lady Hardinge Medical College and Assoc Kalawati Saran Children’s Hospital, NewDelhi, India

ABSTRACT

The prevalence of asthma has increased in developed countries. The efficacy of available drugs in those with severepersistent disease is limited. This has led to a renewed search for the reasons for failures of the existing treatment and fornovel concepts. Treatment with inhaled corticosteroids, and to a much lesser extent theophylline, can reduce the survival ofinflammatory cells including esinophils. Emerging trends in treatments for asthma could include strategies to alter the cytokine/chemokine balance. It is evident that the current ICS are already very efficient and safe, it will be difficult to introduce furtherimproved formulations. Perhaps the most fruitful effort shall be in developing patient friendly easy to use targeted deliverysystems. The newer therapies are planned for the several upstream targets and may have potential to prevent the disease.Various potential therapies are being worked upon like - targeting prevention of T cell activation, modulation of Th-1/Th-2differentiation, inhibition of Th-2 related cytokines, Th-1/Th-2 modulation, inhibition of downstream mediators etc. The newstrategy shall perhaps lie with matching the patients and their disease with the most suitable therapy. [Indian J Pediatr 2008;75 (8) : 845-853] E-mail : [email protected]

Key words : Inhaled corticosteroids; Inflammation; Bronchodilator; Th1/Th2 balance

The prevalence of asthma has increased in developedcountries over the past 40-50 years and similar trends areemerging in developing countries, especially as theyadopt western ways. Different factors underlie thedevelopment of asthma in the different parts of the world,atopy being a common risk factor in developed countrieswhile non atopic factors may be responsible for much ofasthma in the developing countries. We now not onlyhave a better understanding of the mechanism of thedisease but also a great number of proven and possibletreatments. Existing drugs, such as beta-agonists andcorticosteroids, provide relief for sufferers of mild-to-moderate asthma, reversing the acute bronchoconstriction and decreasing the inflammation. The efficacyof these drugs in those with severe persistent disease islimited and the current guidelines often fail to provide ascientific answer to their management. This has also led toa renewed search for the reasons for failures of theexisting treatment and novel concepts of different asthmaphenotypes have emerged,1 which being beyond thescope of this article are not discussed here. Needless tosay, that the inhaled corticosteroids and beta agonists areable to provide relief to most of our patients with asthma.So, is there really a need for a newer drug therapy formost cases of asthma? Innovations to make the current

therapy safer and easier are needed the most. Newertherapies are also looking to shift the goal of theparadigm of treatment from control to cure. The currentreview discusses the newer developments in theestablished as well as innovative futuristic therapies forasthma.

PATHOPYSIOLUS OF ASTHMA ANDTHERAPEUTIC INTERVENTION

The basic alterations of asthma are considered to bebroncho spasm, edema, and hypersecretion. The geneticpredisposition to develop asthma is now well recognizedand the IgE-mediated response to common allergensrepresents the most common form of the disease inchildhood and early adulthood. However, even innonallergic asthma, an immunologic basis for thecondition may be considered, because the pathologicalfeatures and the nature of inflammation are largelysimilar as are high-affinity IgE receptor (Fcå5RI)-bearingcells in bronchial biopsies from atopic and nonatopicasthma.2

Now, it seems likely that new treatments for asthmawould be developed from targeting specific steps in anincreasingly refined model of the immunopathogenesis ofthe disease. In broad terms, this conceptual model (Fig. 1)proposes that allergic sensitization results frompresentation of an innocuous inhaled antigen by anantigen-presenting cell (APC), most likely a dendritic cell,

V. Singh

846 Indian Journal of Pediatrics, Volume 75—August, 2008

to a “T-helper type 0” CD4+ lymphocyte under conditionsfavoring differentiation along the T-helper type 2 (Th2)pathway. Repeated exposure to the same antigen thenpromotes expansion of sensitized Th2 cells, and theirproducts, especially interleukin (IL)-3, IL-4, IL-5, IL-9, andIL-13. These directly or indirectly change the populationand function of immigrant and structural cells in theairways. The changes include attraction anddifferentiation of mast cell precursors, proliferation,attraction, and activation of eosinophils, and IgEproduction by B cells. Possible changes induced byrepeated release of Th2 cytokines also include theelements of “airway remodeling”: vascular neogenesis,proliferation of bronchial smooth-muscle cells,hyperplasia of mucus-secreting cells, and alterations in theextracellular matrix, including deposition of collagenbeneath the basement membrane.3

Treatment with corticosteroids and to a much lesserextent theophylline reduce the survival of inflammatorycells including esinophils thus decreasing inflammationEmerging treatments for asthma could include strategiesto alter the cytokine/ chemokine balance, to skew thecytokine profile away from a Th2 response and towards aTh1 response. Strategies designed to do this, includetherapeutic antibodies or small molecule inhibitorstargeted towards IL-13, IL-4 or their receptors, and theTh1 cytokine IL-12. The interventions to modulate thesignalling pathways involved in asthma are beingevolved . Among these, the mitogen-activated proteinkinase (MAPK) pathway members c-Jun N-terminalkinase (JNK) and p38, the transcription factors nuclearfactor kappaB (NF-kappa B), activator protein-1 (AP-1)and signal transducer and activator of transcription(STAT)-6 are being focused.3,4

INHALED CORTICOSTEROID THERAPY

Inhaled corticosteroids have become indispensable for thetreatment of asthma. The efficacy of the existing inhaledcorticosteroids (ICS) is excellent. Although inhaled routehas allowed the minimization of systemic exposure, there

still remain a number of issues concerning potentialadverse effects. Most of the innovations are now directedtowards decreasing these unwanted effects.

Increased understanding of the potency of differentmolecules and the dose flattening

The active moieties of beclomethasone dipropionate(BDP), ciclesonide, and budesonide are roughlyequipotent at repressing the activity of theproinflammatory transcription factor nuclear factor-βB invitro in A549 lung epithelial cells, while fluticasonepropionate (FP) and mometasone furoate (MF) are bothconsiderably more potent, and are 1,000 times more activethan cortisol. This high potency translates into the use ofsmaller doses to achieve equivalent clinical benefit.However, in vitro potency alone does not establish clinicaldose. The therapeutic index depends upon the deliverymechanism used, lipophilicity as well as the receptorsensitivity of the molecule.

There has been further work on the dose flattening ofthe ICS, for particularly the newer molecules. Holt et alreported that in adolescent and adult patients withasthma, most of the therapeutic benefit of inhaledfluticasone propionate (FP)is achieved with a total dailydose of 100-250 mcg.5 Of equal concerns are severalreports of adrenal crisis – including fatal- with use of highdoses of fluticasone propionate.6,7 There has been a criticalreview of the existing methodology for comparing anddeciding the human dosing of new ICSs and most of thestudies are considered to have serious limitations. Thecurrent international guidelines have thereforedownwardly revised the dosages for ICS for usage amongchildren. In the new guidelines the low daily dose ofbeclomethasone, budesonide as well as FP is 100-200mcg.Dosage over 400- 500 mcg is considered as a very highdose.8

Reducing oral bioavailability

A very large proportion of the dose (40-90%) from themetered or dry powdered inhalers is deposited in themouth and pharynx, and enters the gastrointestinal tract.

Fig. 1. The cellular pathway and cytokines relevant to asthma



The level of systemic exposure to inhaled corticosteroiddrugs thus depends not only on the efficiency ofabsorption through the lung, but also on the uptake of theswallowed dose. The systemic side effects can be reducedby (a) improved delivery devices that deliver a greaterproportion of the drug to the lung (see below), and (b)manipulating the corticosteroids themselves to increasetheir first pass metabolism. BDP still is well absorbedfrom the gut, having an oral bioavailability of 41%.However the oral bioavailability of budesonide is about10% and the most recent generation of compounds- FP,ciclesonide, and mometasone furoate- have an oralbioavailability of less than 1%. Thus essentially all thesystemic exposure from these compounds is a result ofuptake through the target organ, i.e., the lung as almost allof these, except beclomethasone monopropionate (BMP)generate completely inactive metabolites.9

Plasma labile “antedrugs” or “soft” steroids

As discussed above, the current generation of moleculeshas high hepatic inactivation resulting in virtually no oralbioavailability. However, some active drug reaches othertissues by absorption from the lung. A further reductionin systemic exposure therefore requires additionalextrahepatic inactivation and effort has been directedtoward compounds that are rapidly inactivated in plasma.The terms “antedrug” or “soft” drug has been applied tocompounds designed to exert their desired effect locallybut which are inactivated in the circulation to reduceunwanted systemic effects. The ideal antedrug shouldcombine stability in the target tissue with very rapidinactivation in the bloodstream. Corticosteroid esterderivatives are such plasma labile antedrugs but thepresence of esterase activity in the lung makes them lessideal due to potential for premature inactivation in thetarget tissue. Itrocinonide an ester-based antedrug, didnot show great benefit in humans. The glucocorticoidlactone (cyclic ester) antedrugs display the idealcombination of stability in lung tissue with extremelyrapid inactivation in plasma. They are inactivated by theenzyme human serum paraoxonase, an enzyme which isconfined to plasma and liver, making this an idealantedrug inactivation mechanism.10

Lipophilic steroids for better and prolonged lungretention

An alternative way of reducing the systemic liability is tofind ways of retaining compounds in the lung as it mayreduce the maximal concentration to which the systemiccompartment is exposed. FP is considerably morelipophilic than budesonide leading to an 80-fold slowerrate of dissolution in the lung. The high lipophilicity of FPalso generates a higher affinity for lung tissue andtogether these factors increase the time for whichfluticasone propionate is retained within the lung.Budesonide has been reported to form highly lipophilicfatty acid esters in the lung.11 These esters are postulated

to serve as a depot from which the active molecule can beregenerated, and it has been suggested that this propertymay result in both prolonged tissue binding and slowrelease of budesonide, and therefore in improved topicalselectivity and duration of action. Ciclesonide also has asimilar free hydroxyl groups at position 21 and couldundergo the same modification.10

The plasma protein binding of mometasone furoateand the active principle of ciclesonide have been reportedto be between 98 and 99%. The high safety marginobserved for these drugs, for example an insignificantdegree of plasma cortisol suppression, has been linked tothis pronounced plasma protein binding. However,pronounced tissue binding in the lung might also reducethe free concentration of the drug at the site of action.More studies are needed to understand the clinicalimplication of this.

Prodrug approach

In addition to the adverse effects of systemic absorption,the oral deposition of steroids, is associated with local sideeffects like candidiasis, dysphonia. This can be obviatedby the use of spacers, gargling or by the use of prodrugswhich only get activated locally in the lung . Both BDPand ciclesonide use this approach. However, there is littleevidence to suggest that this leads to a significantreduction in local side effects. 10

Disassociated steroids

The effect of the corticosteroids at the cellular level mayoccur through the transactivation of the genes or by thetrans-repression of the activated pro-inflammatory genes.The transactivation pathways are thought to induceundesired side effects, while transrepression oftranscription factors is linked to the desired effects ofcorticosteroids on asthma. The current research istherefore focused to identify molecules which havedifferentially high trans repression activity completelydisassociated from its trans-activation role. Vayssie‘re etal reported RU24858 as first such compound withdissociated activity.12 While this compound showed invivo anti-inflammatory activity comparable toprednisolone, there was no improvement in side effectparameters such as osteoporosis, weight reduction, orthymic involution. It was subsequently shown thatRU24858 had stronger in vivo transactivation activity,indicating that the in vitro assays used to characterize thecompound were likely to have different couplingefficiency.12

Other new drugs such as A276575 and AL438,reportedly have improved effect to side-effect ratios.13

Animal studies using different models have howeverbeen inconclusive.14 ZK216348 is another compoundclaimed to have a markedly superior side effect profile asa result of its dissociation between transactivation andtransrepression, based on measurement of blood glucose

V. Singh


and spleen involution. Interestingly, the effects of samecompound on the hypothalamic-pituitary-adrenocortical(HPA) axis suppression was similar to prednisolone. Thismay suggest that a transpression selective corticosteroidmight not necessarily have an improved therapeuticindex as far as HPA axis effects are concerned.10,14

Better delivery devices for ICS

From the foregoing discussion, it is evident that thecurrent ICS are already very efficient and safe, it will bedifficult to introduce further improved formulations.Perhaps, the most fruitful effort shall be in developingpatient friendly easy to use targeted delivery systems. Thepatients want devices that are easy to operate correctly,provide clear feedback on the success of the inhalationmanoeuvre and offer as many inhaled medications aspossible in the same inhaler.

Metered-dose inhalers currently in vogue haverelatively small (10%) pulmonary deposition efficiencies.The deposition efficiency of dry powder inhalers isequivalent or only somewhat higher (up to 30% for theturbohaler). It is obvious that improved pulmonarydeposition will favor pulmonary selectivity, especially fordrugs with high oral bioavailability, such asbeclomethasone dipropionate. The transition fromchlorofluorocarbon- to hydrofluoroalkane-based metered-dose inhalers resulted in valve and actuator redesigns andthe use of solution- rather than suspension-based systems.These changes yielded smaller aerosol particle sizes,different aerosol plume characteristics (e.g., soft plume),and higher pulmonary and peripheral deposition.14,15,

Ederle et al showed that patients switching to the moreefficient hydrofluoroalkane beclomethasone dipropionatepreparations were able to reduce their daily dose by half.16

More drug to the peripheral part of the lung with HFAinhalers might be beneficial in asthma as these regions areinvolved in inflammation and remodeling of the lung.Future studies are needed to evaluate the benefits andrisks of more peripheral deposition in asthma therapy.Higher peripheral lung deposition might also results infaster pulmonary absorption, faster spillover into thesystemic circulation, and reduced pulmonary selectivity.17

Electronic or mechanical breath actuation mechanismshave been incorporated into some devices or developedas add-on devices to improve hand-breath coordinationwith MDIs. Examples are Smart Mist, Easibreathe, andMaxair Autohaler.17 Another innovation has been newDry-powder inhalers (DPIs), such as the Novolizer(MEDA AB, Solna, Sweden) which eliminates the need forcoordination as they are breath activated. The Novolizerhas multiple visual (red, green, yellow) and acousticfeedback signals which assure the patient that theinhalation was performed correctly. An ‘‘intelligent’’counter keeps track of the correctly executed inhalations.Novolizer achieved more pulmonary deposition and lessoral deposition than the Turbuhaler when both devices

were used correctly.17,18

WHAT IS NEW WITH THEOPHYLLINES?

Methylxanthines are widely used in the treatment ofasthma. Being one of the few drugs that can beadministered orally, they are especially helpful inresource restricted settings. Theophylline, a commonlyused non specific phosphodiesterase inhibitor,methylxanthine, is less preferred drug due to a widerange of adverse effects and a narrow therapeutic index.At present the GINA guidelines suggest its use only as anadd-on therapy or as a poor replacement for ICS in mildpersistent disease.

Now we also understand that theophylline activateshistone deacetylases (HDACs) and therefore suppressesthe expression of pro-inflammatory genes in the airways.This effect is seen at therapeutic concentrations oftheophylline (10-6–10-5 M) but is lost at higherconcentrations (10-4 M). The effect is different from that ofcorticosteroids, as there appears to be a relatively directactivation of HDAC. By contrast, the effects ofcorticosteroids are due to recruitment of HDAC to theactive transcription site, and there is no direct effect onHDAC activation. The mechanism whereby lowconcentrations of theophylline activate HDAC are not yetknown, but it is not mediated by either phosphodiesterase(PDE) inhibition or adenosine receptor antagonismbecause PDE inhibitors (nonselective, PDE4 and PDE3inhibitors). Even adenosine A1- and A2-receptorantagonists do not mimic this action of theophylline.Theophylline appears to have an effect that is differentfrom those of corticosteroids, and it may therefore be auseful drug to combine with low-dose inhaled steroids. Inaddition, its low cost makes low-dose theophylline incombination with a generic inhaled corticosteroid themost cost effective way to manage persistent asthma indeveloping countries.19

Because of problems with side effects, there have beenattempts to improve on theophylline, and recently therehas been increasing interest in the development ofselective PDE inhibitors. Selective PDE inhibitors have thepossibility of improving the beneficial and reducing theadverse effects of theophylline, although existinginhibitors appear to be limited by the same side effects astheophylline. PDE4 inhibitors have particularly beenshown to reduce the infiltration of esinophils and airwayhyper responsiveness in animal models of asthma. Theymay have potential anti-inflammatory andantimodulatory effects in the pulmonary system.19

Roflumilast is a PDE-4 inhibitor which, has been studiedas an oral tablet in doses of 250 or 500µg/day in adults.Animal data and clinical trials have demonstratedroflumilast’s efficacy and safety as an antiinflammatoryand antimodulatory agent for use in asthma. Its exactplace in the therapy is as yet not established.20



Doxofylline, a new entrant to the Indian market, is nota specific PDE isoenzyme inhibitor. Studies in animalsand human adults reported it to have similar efficacy butless side effects as compared to theophylline. However,there is a paucity of studies in children with asthma.Dosage recommended for children >6 yrs of age is 6 mg/Kg/dose BID. Doxofylline produces stable serumconcentrations, hence plasma monitoring is required onlyin patients with hepatic insufficiency and intolerance toxanthine drugs.21

WHAT IS NEW WITH LONG ACTING βββββ2 AGONISTS?

The U.S. Food and Drug Administration decided to placeblack box safety warnings on long-acting adrenergicbronchodilators (LABA) alone or in combination withICSs. This action generated a plethora of review articlesand editorials about these agents. However, the case ofwarning on LABA with ICS seems to be that of extremecaution because so far the increased mortality has beenreported in patients who have been using LABAs withoutICS. Most guidelines like GINA 2007,8 Expert Panelreport 3 (2007)22 continue to treat the combination of ICSand LABA as a synergistic combination which haspotential to decrease the ICS dose needed for control.

The LABA -formoterol has an onset of bronchodilatingeffect comparable with albuterol in rapidity. Thisdifferentiates the molecule from salmeterol whosebronchodilating action is slower in onset. Therefore, acombination of formoterol with ICS has the capacity toprovide rapid acute relief of bronchoconstriction and theconcurrent anti-inflammatory actions when asthmaexacerbation began. A recent study reported that adultpatients with mild asthma could be treated successfullywith once-daily combined fluticasone 100 mcg andsalmeterol 50mcg.23 Such a combination is greatly usefulin improving patient adherence to therapy due to once-daily schedule.

Newer LABA—The Extended LABAs

There have been reports of two extended newer LABA inwhich their bronchodilating effect lasts for 24 hour,Indacaterol and Carmoterol.24 They both have a rapidonset of bronchodilator activity. The likelihood is thatthese extended LABA agents will not be developed assingle agents for asthma care, but as part of a combinationwith an ICS. Such a combination of 24-hourbronchodilators along with an ICS may be useful to treatasthma of greater severity and maintain a relatively lowadverse reaction profile.

NEWER TARGETED STRATEGIES FOR ASTHMA

The ICS and LABA work quite downstream in the

pathogenic framework of asthma. The newer targets areplanned for the several upstream targets and may havepotential to prevent the disease. The currentunderstanding of the disease suggests that Th1 /Th2imbalance is the fundamental abnormality responsible forthe genesis and persistence of inflammation in asthma.Prevention or reversal of Th2 phenotype probably canprevent or cure this disease. Disruption of the Th2lymphocyte induced allergic inflammation at its origin isthe current focus of asthma therapy research. Possibletherapeutic interventions include (a) inhibition of Th2response, targeting the T cells or Th2 cytokines; (b)inhibition of IgE which is produced as a downstreameffect of the Th2 cytokines (c) strengthening Th1 pathwayis another strategy. The following section details thevarious potential therapies which have are being workedupon.

Targeting prevention of T cell activation

T-cell immunomodulatorsCyclosporin-A and the functionally related Tacrolimus arepowerful immunosuppressant agents widely used toprevent immune rejection in organ transplantation. Incorticosteroid dependent asthma, low-dose cyclosporin-A improved lung function allowing for a 62% reduction inoral steroid dose requirement, albeit at the expense ofadverse effects which would not prove tolerable in milddisease. Meta-analysis of controlled trials confirmssteroid-sparing effect for Methotrexate, a folateantagonist, in asthma, but shows no significant evidenceof benefit on lung function or symptoms. In clinicalpractice, these immunomodulators are only modestlyeffective in a proportion of patients.25

Suplatast tosilate is a novel immunomodulator whichselectively prevents the release of IL-4 and IL-5 from Th-2 cells. It has shown to reduce bronchial esinophilia inanimal models of bronchial hyper-responsiveness. It hasthe added advantage of providing improvement inpulmonary function and symptom control, and decreasein the dose of inhaled corticosteroid. This molecule hasbeen launched for treatment of asthma in Japan.26

Anti-CD4 monoclonal antibody

The recombinant monoclonal antibodies (MAB) againstCD4+ T-cells result in ablation of airway hyper-responsiveness and airway esinophilia. A single dose ofanti-CD4 monoclonal antibody that reduces circulatingCD4+ T-cells in severe corticosteroid dependent asthmaled to an improvement in morning and evening peakexpiratory flows but did not significantly impact onasthma symptoms. However there are concerns regardingthe resultant risk of opportunistic infection and neoplasiaafter induction of CD4 lymphopenia.27

Modulation of Th-1/Th-2 differentiation

Attempts to alter Th-l/Th-2 balance by enhancing Th-1, or

V. Singh


abrogation of Th-2 responses have been the major thrustof immune approaches to the prevention and treatment ofallergies and of asthma. This includes administration ofcytokines that will induce activation of Th-1 pathways(e.g. IFN-γ, IL-12 and IL-18) or blocking antibodies thatinhibit the effect of Th-2-related cytokines (e.g. anti-IL-4,anti-IL-5, anti-IL-9, and anti-IL-13). Vaccination and DNAoligonucleotides have also been used to achieve thismodulation.

Interferon-γ (INF-γ)

IFN-γ, released from CD4+ (Th-1) and CD8+ (TC2) cells, isa critical factor regulating the balance of Th-l/Th-2development. It exerts an inhibitory effect on Th-2 cells aswell as on IL-4- induced IgE synthesis by B-cells.Inhalation of IFN-γ by non-asthmatic humans increasesepithelial lining and BAL fluid IFN-γ levels but does notaffect serum levels. Using this route can obviate theassociated systemic effects.28 Subcutaneous IFN-γ therapyin steroid dependent asthma has also been evaluated, butit showed no effect on lung function or treatmentrequirement although the circulating esinophil weresignificantly reduced.29

Interleukin-12 (IL-12)

IL-12, produced by antigen-presenting cells, enhances thegrowth of activated T and NK cells, stimulating them toproduce IFN-γ. IL-12 can regulate Th-1 cell differentiationwhile suppressing the expansion of Th- 2 cell clones byearly priming of undifferentiated Th-0 cells for IFN-γsecretion. In a Phase I trial of IL-12 in asthma, a significantreduction of peripheral esinophils and trend to reductionin airway esinophils was observed without effect onallergen-induced early or late phase responses. Significanttoxicity including arrhythmias, liver functionabnormalities and flu-like illness limits its potential utilityin asthma.30

Inhibition of Th-2 related cytokines

The reciprocal approach—of antagonizing the actions ofTh2 cytokines, rather than of enhancing the production oraction of Th1 cytokines—appeared to have great promise.sIL-4R and Anti IL-5 were investigated for this approach.

Recombinant soluble IL-4 receptor (sIL-4R)

IL-4 induces polarisation of the Th-0 cell to the Th-2phenotype as well as isotype-switch from IgM to IgEsynthesis by B-cells. It up-regulates IgE receptors andVCAM1 expression on vascular endothelium therebyfacilitating endothelial passage and accumulation ofesinophils and basophils. The recombinant soluble IL-4receptor (sIL-4R) mimics the cell-surface receptor andbinds / sequestrates free IL-4. acting as an IL-4 receptorblocker.31

Another approach to inhibition of IL-4 production is totarget the control of transcription factors of the IL-4 gene.

STAT-6 responsive elements are found in the promoterregion of IL-4 inducible genes and are expressed atabnormally high levels in the epithelium of severeasthmatics. The STAT-6 directed antisenseoligonucleotides have shown to markedly down-regulategermline Cε mRNA levels, reflecting inhibition of IL-4-dependent IgE isotype switching.32

Anti- lnterleukin-5 monoclonal antibody

Esinophil mobilisation and trafficking, their maturationand maintenance are largely promoted by the Th-2cytokine, IL-5, making it an attractive therapeutic target inesinophilic conditions. Two humanised forms of anti-IL-5 (SB-240563 and Sch 55700) monoclonal antibodies (Mab)have been studied. The injection of anti–IL-5 Mab had anaction was shown by a striking, sustained reduction inblood esinophils, and by a similarly impressive reductionin sputum esinophil numbers 24 h after antigen challenge.These changes were not, however, associated with effectson the early or late fall in FEV1, nor on the increase inbronchial reactivity caused by bronchial challenge. 25,33

These disappointing findings do not necessarilyexclude IL-5 or esinophil-mediated actions as being ofcentral importance in asthma. It is also true that the fall inblood esinophils does not necessarily imply a similar fallin tissue esinophilia. One recent report stated that anti–IL-5 Mab reduced blood esinophils by 85%, but tissueeosinophils by only 55%.34 And the lack of effect on acutechanges in airway caliber or bronchial reactivity does notrule out other important therapeutic actions, such asinhibition of airway remodeling. Another recent reportstated that anti–IL-5 Mab treatment caused significantreductions in esinophilia and significant decreases in thethickness and density of tenascin staining in the reticularbasement membrane.35

lnterleukin-13

This cytokine shares 70% sequence homology with IL-4 .However, when administered after the initial allergensensitisation, this agent had no effect on serum IgElevels.31

Th-1/Th-2 modulation

By vaccinationAn indirect way of modulating Th-l/Th-2 balance hasbeen to boost innate immunity by the use of vaccines,particularly for the redirection of the Th- 2 response infavour of Th-1 response. The potential benefit of BCGvaccination in atopic diseases was first raised by a studyin Japanese schoolchildren, which suggested a role forearly mycobacterial exposure in subsequent developmentof atopic responsiveness. Experimental models havesupported this concept using the non-pathogenicmycobacterial products of Mycobacterium bovis andMycobacterium vaccae. Clinical trials evaluatingimmunization with M vaccae (which is not pathogenic to



humans) in asthma and rhinitis are in progress with earlyresults showing efficacy.36

Using DNA oligonucleotides

This novel type of therapy for asthma, DNA-basedtherapy, aims at enhancing the Th1 response, decreasingthe Th2 response, or down-regulating certain RNAtranscripts to modulate the immunopathogenesis ofasthma. The strategies used are using immunos-timulatory oligonucleotides, DNA gene therapy,antisense oligonucleotides, and RNA interference.

Bacterial DNA has a higher frequency of CpGdinucleotide (1 in every 16 dinucleotides) than vertebrateDNA (1 in every 125 dinucleotides). Furthermore, 70% to90% of the cytosine bases at position 5 in CpGdinucleotides are methylated in mammals as comparedto < 5% in bacterial DNA. Therefore, vertebrates havedeveloped some immune defense against bacteriathrough the recognition of unmethylated CpGdinucleotides. CpG ODNs trigger the production of IFN-γ, which inhibits the proliferation of Th2 cells and inducesa Th1 environment. Thus, CpG ODNs are extremelyeffective at inducing a Th1-like immune response andpreventing Th2 immune stimulatory effects which causeallergic asthma.37

Interim results from phase I/II clinical studiesinvolving about 300 individuals suggest that CpG ODNsare well tolerated and activate the immune system, whichseems promising for the treatment of allergic airwayinflammation.37 Gauvreau et al evaluated the therapeuticeffect of 1018 ISS (a “K” type CpG ODNs) in mildpersistent asthma patients. They found that weeklyinhalation of 1018 ISS for 1 month using a nebulizersignificantly increased the expression of IFN-γ and IFNinducible genes. However, 1018 ISS did not inhibit the fallin FEV1 or other characteristic responses to inhaledallergen challenge.38 The authors did not report anysignificant adverse effects. More studies are awaited forthis potential modality for preventing allergic asthma.

Inhibition of downstream mediators

Anti –IgEA new therapy based on the scientific understanding ofthe pathogenesis of asthma that has borne fruit isantagonism of IgE with a humanized monoclonalantibody (rhuMAb-E25, or “omalizumab”). The studieson human subjects show that treatment with omalizuablowers serum levels of free IgE, the number of IgEreceptors expressed on basophils, and antigen-stimulatedhistamine release. They show also that anti-IgE Mabtreatment reduces the early and late responses and the risein bronchial reactivity and in sputum esinophilia causedby antigen challenge.39 And phase 3 studies involvingnearly 1,500 patients with moderate-to-severe asthmashow that anti-IgE Mab treatment not only improvesasthma control and lowers exacerbation rates when added

to continued corticosteroid therapy, but also maintainsthese benefits even while enabling significant reduction incorticosteroid dose.40 It is approved for use in asthmapatients aged 12 and older who have moderate to severepersistent asthma, and who have tested positive for aperennial aerial allergens e.g. such as pollen, grass, ordust. Milgrom et al reported its efficacy in about 330children between 6-12 years.41 Current GINA andEPR 3 guidelines recommend use of anti-IgE in severepersistent atopic asthma in adults in an effort to decreasehigh doses of steroids.8,22 Omalizumab (Xolair®) can causepotentially life-threatening allergic reactions includinganaphylaxis. Nearly 15% of the patients having allergicreactions required hospitalization. No deaths have beenreported. US FDA alert warns that patients can have adelayed reaction from two to 24 hours or longer afterinjection.42\

OTHER POTENTIAL THERAPIES

Inhibition of esinophil migration and activationCCR3 receptors are expressed on basophils, esinophils,mast cells, and Th2 cells; CCR2, CCR4, and CCR8 areexpressed on T-helper lymphocytes. CCR3 ligands includeeotaxin-1, eotaxin-2, eotaxin-3, RANTES (regulated uponactivation, normal T-cell expressed and secreted),macrophage inhibitory protein (MIP)-1, MIP-2, and MIP-3. Several low-molecular-weight CC and CXC inhibitorshave been developed. CCR3 antagonists inhibit antigen-induced increases in BAL esinophilia and airwayreactivity in sensitized mice, rats, and monkeys. 25, 31

Future studies may find there usefulness in managingasthma.

Adenosine receptor antagonism-respiratory antinsenseoligonucleotide (RASON)

Adenosine challenge provokes broncho constriction,probably through stimulation of the release of mast cellmediators, rather than through direct binding to receptorson airway smooth muscle, as histamine and methacholineare thought to do.43 Respirable antisense oligonucleotides(RASON)s are designed to hybridize in vivo, to their‘sense’ counterparts which are found within targetmessenger RNAs. This hybridization blocks the templateproperties of the messenger RNA, preventing itstranslation into the protein for which it codes. AnyRASON greater than 14 bases in length that is not targetedto highly conserved or repetitive-type sequence structuresshould theoretically hybridize uniquely to one and onlyone messenger RNA. RASONs are effective at smallerdoses since they are delivered as aerosols directly to thelungs. This also decreases the potential for non-antisensesystemic side effects and toxicity.37 The lung is uniquelylined with surfactant, which enhances the uptake ofoligonucleotides into cells.

The first developed and extensively studied RASON is

V. Singh


EPI-2010. It is a 21-mer RASON targeting the initiationcodon of the adenosine A1 receptor mRNA. EPI-2010reduces the number of adenosine A1 receptors inbronchial smooth muscles and attenuates AHR in rabbitsand primates. In phase I clinical trials conducted in theUK, EPI-2010 was effective at single inhaled doses, thusreducing the need for a bronchodilator to control asthmasymptoms. Furthermore, the duration of effect was 6.8days (range 4~11 days) with a once-per-week treatment.EPI- 2010 was safe and well tolerated, without anycoagulation or cardiovascular side effects.44 However, thephase II clinical trials performed in patients withmoderate persistent asthma who were receiving inhaledcorticosteroids showed insufficient effects. Therefore, thedevelopment of EPI-2010 was discontinued.45,46

Tianeptine

Increased levels of f-5HT in plasma, during asthmaattacks, have been shown to be associated with clinicalseverity and pulmonary function. Tianeptine (a serotoninuptake enhancing drug, which reduces plasma f-5HT) canevoke a dramatic and sudden decrease of both clinicalrating and f-5HT plasma levels as well as an increase inpulmonary function. Most of the work with this drugcomes from a single group in Venezuela. Further studiesare needed to evaluate this drug fully.47

While the recent developments indicate that thespecific understanding of the pathogenesis and theelements involved may help us identify therapy whichwill cure or prevent asthma, yet the promises made onthe bench side are yet to be realized by the bed side.Possibly, in future we will have a large armamentariumbut few of these will be useful for most patients. The newstrategy shall perhaps lie with matching the patients andtheir disease with the most suitable therapy. This alsoraises a pertinent question for those in the developingworld. How relevant is all this to our needs? With theincreasing realization that the asthma in the developingworld is more often non-atopic and the newer therapiesresearched in the west are more focused on the allergicmodel, the least we can and we should do is not to blindlyfollow all this information coming our way.

REFERENCES

1. Bush A. Phenotype specific treatment of asthma in childhood.Pediatric Respir Reviews 2004; 5 : S93–S101.

2. Bousquet J, Jeffery PK, Busse WW et al. Asthma. Frombronchoconstriction to airways inflammation and remodeling.Am J Respir Crit Care Med 2000; 161 : 1720-1745.

3. Pahl1 A, Szelenyi I. Asthma therapy in the new millennium.Inflamm Res 2002; 51 : 273-282.

4. Mimi LK, Collin, P. Childhood asthma as an allergic disease:rationale for the development of future treatment. Eur JPediatr 2001; 160 : 696-704.

5. Holt Shaun, Suder Aneta, Weatherall Mark, Cheng Soo,Shirtcliffe Philippa, Beasley Richard. Dose-response relation of

inhaled fluticasone propionate in adolescents and adults withasthma: meta-analysis. BMJ 2001; 323 : 1-8.

6. Todd GR, Acerini CL, Ross-Russell R et al. Survey of adrenalcrisis associated with inhaled corticosteroids in the UnitedKingdom. Arch Dis Child 2002; 87 : 457-461.

7. Paton J, Jardine E, McNeill E et al. Adrenal responses to lowdose synthetic ACTH (Synacthen) in children receiving highdose inhaled fluticasone. Arch Dis Child 2006; 91 : 808-813.

8. Global Strategy for Asthma Management and Prevention,Global Initiative for Asthma (GINA) 2007. Available from:http://www.ginasthma.org.

9. Barnes PJ, Pedersen S, Busse WW. Efficacy and Safety ofInhaled Corticosteroids New Developments. Am J Respir CritCare Med 1998; 157 : S1–S53.

10. Biggadike K, Uings Iain, Farrow Stuart N. DesigningCorticosteroid Drugs for Pulmonary Selectivity. Proc AmThorac Soc 2004; 1: 352–355.

11. Edsba¨cker S, Brattsand R. Budesonide fatty acidesterification: a novel mechanism prolonging binding toairway tissue. Review of available data. Am Allergy AsthmaImmunol 2002; 88 : 609–616.

12. Vayssie‘re BM, Dupont S, Choquart A, Petit F, Garcia T,Marchandeau C et al. Synthetic glucocorticoids that dissociatetransactivation and AP-1 transrepression exhibit anti-inflammatory activity in vivo. Mol Endocrinol 1997; 11 : 1245-1255.

13. Coghlan MJ, Jacobson PB, Lane B, Nakane M, Lin CW, ElmoreSW et al. A novel anti-inflammatory maintains glucocorticoidefficacy with reduced side effects. Mol Endocrinol 2003; 17 :860–869.

14. Belvisi MG, Wicks SL, Battram CH, Bottoms SEW, Redford JE,Woodman P et al. Therapeutic benefit of a dissociatedglucocorticoid and the relevance of in vitro separation oftransrepression from transactivation activity. J Immunol 2001;166 : 1975–1982.

15. Agertoft L, Laulund LW, Harrison LI, Pedersen S. Influence ofparticle size on lung deposition and pharmacokinetics ofbeclomethasone dipropionate in children. Pediatr Pulmonol2003; 35 : 192-199.

16. Ederle K. Improved control of asthma symptoms with areduced dose of HFA-BDP extrafine aerosol: an open-label,randomised study. Eur Rev Med Pharmacol Sci 2003; 7 : 45–55.

17. Hochhaus Gu¨nther. New Developments in Corticosteroids.Proc Am Thorac Soc 2004; 1 : 269-274.

18. Helgo Magnussen Novolizer: How does it fit into inhalationtherapy? Curr Medic Research Opinion 2005; 21, S39-46.

19. Barnes Peter J. Theophylline New Perspectives for an OldDrug. Am J Respir Critic Care Medi 2003; 167: 813-818.

20. Karish Sarah B, The Potential Role of Roflumilast: The NewPhosphodiesterase-4 Inhibitor. Annals Pharmacotherapy 2006;40 : 1096-1104.

21. Sankar Jhuma, Lodha Rakesh, Kabra SK. Doxofylline: Thenext generation methylxanthine. Ind J Pediatrics 2008; 75 : 251-254.

22. Expert Panel Report 3: Guidelines for the Diagnosis andManagement of Asthma—Full Report, 2007 as downloaded inJune 2008from http://www.nhlbi.nih.gov/guidelines/asthma/index.htm

23. The American Lung Association Clinical Research Centers.Randomized comparisons of strategies for reducing treatmentin mild persistent asthma. N Engl J Med 2007; 356 : 2027-2039.

24. Mansfield Lyndon E. The future of the long-acting beta-adrenergic bronchodilators in the treatment of asthma. AllergyAsthma Proc 2008; 29 : 103-108.

25. Stirling RG, Chung KF. Future treatments of allergic diseasesand asthma. Bntish Medical Bulletin 2000;56: 1037-1053

26. Tamaoki J, Kondo M, Sakai N et al. Effect of Suplatast tosilate,



a TH2 cytokine inhibitor, on steroid-dependent asthma: adouble blind randomised study. Lancet 2000; 356: 273-278.

27. Kon OM, Sihra BS, Compton CH, Leonard TB, Kay AB,Barnes NC. Randomised, doseranging, placebo-controlledstudy of chimeric antibody to CD4 (keliximab) in chronicsevere asthma. Lancet 1998; 352 : 1109-1113.

28. Jaffe HA, Buhl R, Mastrangeh A et al. Organ specific cytokinetherapy. Local activation of mononuclear phagocytes bydelivery of an aerosol of recombinant interferon-gamma to thehuman lung. Clm Invest 1991; 88 : 297-302.

29. Boguniewicz M, Schneider LC, Milgrom H et al. Treatment ofsteroid-dependent asthma with recombinant interferon-gamma. Clm Exp Allergy 1993; 23: 785-790.

30. O’Connnor B, Hansel T, Holgate S, Barnes P. Effects ofrecombinant human IL-12 on allergen induced airwayinflammation and the late response. Am J Resptr Cnt Care Med2000; 161: A592.

31. Boushey HA. New and Exploratory Therapies for AsthmaChest 2003; 123 : 439S-445S.

32. Hill S, Herlaar E, Le Cardinal A, van Heeke G, Nicklin P.Homologous human and murine antisense oligonucleotidestargeting Stat6. Functional effects on germline c-epsilontranscript. Am J Respir Cell Mol Biol 1999; 21: 728-737.

33. Kips JC, O’Connor BJ, Langley SJ et al. Results of a phase I trialwith SCH55700, a humanized anti-IL-5 antibody, in severepersistent asthma. Am J Respir Crit Care Med 2000; 161: A505.

34. Gregory B, Kirchem A, Rankin S et al. Exposure of humaneosinophils to IL-5 down-regulates IL-5R and IL-5responsiveness: a possible explanation for relative resistanceof airway eosinophils to anti-IL-5 therapy [abstract]. Am JRespir Crit Care Med 2002; 165: B50

35. Flood-Page, O, Menzies-Gow, A, Phipps, S et al Reduction oftissue eosinophils in mild atopic asthmatics by an anti-IL-5monoclonal antibody (mepolizumab) is associated withinhibition of tenascin deposition within the bronchialepithelial basement membrane [abstract]. Am J Respir Crit CareMed 2002; 165: B42.

36. Farooqi IS, Hopkin JM. Early childhood infection and atopicdisorder. Thorax 1998; 53 : 927-932.

37. Wang Li-Chieh, Lee Jyh-Hong, Yang Yao-Hsu, Lin Yu-Tsan,Chiang Bor-Luen New Biological Approaches in Asthma:DNA-Based Therapy. Current Medicinal Chemistry 2007; 14:1607-1618.

38. Gauvreau GM, Hessel EM, Boulet LP, Coffman RL, O’ByrnePM. Immunostimulatory sequences regulate interferon-inducible genes but not allergic airway responses. Am J RespirCrit Care Med 2006 174: 15-20.

39. Chang TW. The pharmacological basis of anti-IgE therapy.Nat Biotechnol 2000; 18 : 157-162

40. Soler M, Matz J, Townley R et al. The anti-IgE antibodyomalizumab reduces exacerbations and steroid requirement inallergic asthmatics. Eur Respir J 2001; 18 : 254-261.

41. Milgrom H, Berger W, Nayak A, Gupta Niroo, PollardStephen et al. Treatment of childhood asthma withantiimmunoglobulin E antibody (omalizumab). Pediatrics2001; 108 : e36

42. XOLair FDA alert as downloaded June 2008 from theirwebsite http://www.fda.gov/cder/drug/InfoSheets/HCP/omalizumabHCP.pdf

43. Holgate S. Adenosine provocation: a new test for allergic typeairway inflammation. Am J Respir Crit Care Med 2002; 165 :317-318.

44. Ali, S, Leonard SA, Kukoly CA, Metzger WJ, Wooles WR,McGinty JF et al. Absorption, Distribution, Metabolism, andExcretion of a Respirable Antisense Oligonucleotide forAsthma. Am J Respir. Crit Care Med 2001; 163: 989-993.

45. Nyce, J. Respirable antisense oligonucleotides: a new, thirddrug class targeting respiratory disease. ImmunotherapyCurrent Opinion Allergy & Clinical Immunology 2002; 2: 533-536.

46. Nyce JW, Metzger WJ. DNA antisense therapy for asthma inan animal model. Nature 1997; 385 : 721-725.

47. Lechin F, van der Dijs Bertha, Lechin A E,. Boushey H ATianeptine: A New exploratory Therapy for Asthma. Chest2004; 125 : 348-349.

what is new in the management of childhood asthma?

Documents