Annals of African Medicine Annals of African Medicine Society ISSN: 1596-3519 Vol. 6, Num. 1, 2007, pp. 1-6

Annals of African Medicine, Vol. 6, No. 1, 2007, pp. 1-6

Review

Management of Asthma in Adults: Current Trends and Future Directions 

A. K.  Bello and C. H.  Njoku 

Department of Medicine, Usmanu Danfodiyo University, Sokoto, Nigeria

Reprint requests to: Dr C. H. Njoku, Department of Medicine, College of Health Sciences, Usmanu Danfodiyo University, P. M. B. 2254, Sokoto, Nigeria. E-mail: chnjoku2000@yahoo.com

Code Number: am07001

Abstract

Bronchial asthma has witnessed a significant increase in its prevalence in the past decade. Considerable morbidity and significant mortality has been associated with it and this has been matched by increased scientific research into new methods of therapy to supplement or replace the traditionally known treatment modalities. A search for old and new literature on asthma management in adults necessitated forage in the library for old works and an internet search into relevant websites to download several works on asthma from which those relevant to this article were selected. Evidences supporting current asthma therapies including some non-pharmacological measures of intervention and alternative approaches were highlighted. Some novel interventions that may be useful in the future management of asthma were discussed. Some novel therapeutic agents acting on specific components of the inflammatory pathways in asthma are emerging. The future management of asthma may involve the use of these newer agents in combination with more established therapies. For successful management of asthma, patient’s education and involvement are essential.

Key words: Bronchial asthma, management, adults

Résumé

Ll’asthme bronchique a connu une augmentation significative à son fréquence au cours de la décennie passée. On l’avait associer avec une morbidité considérable et une mortalité significative et cellesci ont été égaler avec une recherche scientifique augmentée sur des nouvelles méthodes thérapeutiques pour supplementer ou remplacer les modalités du traitement connu traditionnellement.Une cherche pour l’ancienne ou la nouvelle littérature sur la gérance de l ;asthrue chez les adultes a nécessite un fourrage dans la bibliothéque pour des anciens travaux aussi qu’une cherche sur l’internet aux websites pertinent pour rétirer plusieurs travaux sur l’asthme. C’est à partir de ces travaux que ceux qui sont pertinent à  cet article sont selectionés. Les preuves en faveur des thérapies actuelles de l’asthme y inclus quelques mesures pharmacologique d’intervention et des autres approches sont souliognées. Quelques interventions nouvelles qui peuvent être utile dans l’avenir pour la gérance de l’asthme sont aussi discutées. Quelques nouvelles agents thérapeutiques qui agir sur les composantes spécifiques des chemins inflamatoires en asthme s’émerge. Dans l’avenir la gérance de l’asthme peut entrainer l’emploie de ces nouveaux agents en association avec les thérapies les plus établir. Pour réussir à la gérance de l’asthme, l’education et la participation du malade est essential.

Mots clés: L’asthme bronchique, la gérance, les adultes

Introduction

The past decades have witnessed a spectacular increase in the prevalence of asthma globally, with associated significant use of healthcare resources. As far back as 1860, Henry Hyde Salter, a Physician at Charing Cross Hospital in London described asthma as paroxysmal dyspnoea of a peculiar character with intervals of healthy respiration in between attacks. ^{1 - 3} He drew attention to the musical rhonchi that characterised asthmatic bronchoconstriction, and  identified its cellular basis, which was only fully elucidated after the development of eosin stain by Paul Ehrlich in 1875. ⁴ The pathological basis was further described by Huber and Koessler in 1922. ⁵imilarly, another significant milestone is the characterisation of its trigger factors by Sir William Osler in the early part of the 19^th century. ⁶

Asthma is associated with variable airflow obstruction, airwayhyper-responsiveness, and chronic airway inflammation. It can cause considerable morbidity and asignificant mortality. It is defined as reversible airway obstruction associated with inflammation and bronchial hyper-responsiveness. ⁷ The airway hyper-responsiveness is induced by a variety of local stimuli involving biochemical pathways of histamine, leukotrienes and prostaglandins. Various risk factors are associated with the development of asthma. These include familial predisposition, maternal smoking, ethnicity, socio-economic status and gender (male sex). ^{7, 8}

National and international guidelines have developed a stepwise approach to management, with treatmentincrement until asthma control is achieved and stepped downonce control has been maintained for several months. ^{7, 8} Currently available anti-inflammatory and bronchodilatordrugs are very effective and a good asthma control can be achievedfor most patients using these agents. A significant minority, however, will havemore severe persistent asthma which is difficult to manage andwhich may require alternative approaches. New drugs whichimprove control and outcome, with minimal sideeffects, or improve compliance are therefore needed. Somenew classes of drugs, which may fill these roles, are currentlyunder investigation. This review aims to discuss the evidence supportingcurrent asthma therapies including some non-pharmacological measures of intervention,and alternative approaches where appropriate, and finallydiscuss some novel interventions under development that may be useful in the futuremanagement of asthma.

Lifestyle modification and other non-pharmacological strategies in the management of asthma

Changes in attitude, behaviour and lifestyle may play a significant role in the management of asthma. ^{9, 10}

Smoking

Cigarette smoking in adults with asthma is associated with anaccelerated decline in lung function, increased symptoms severityand exacerbation of frequency of attacks in addition to impaired response to inhaledcorticosteroids. ¹¹ Although studies confined to populationsof patients with asthma have not been done, smoking cessationclearly has a number of important health benefits which arelikely to be particularly important to patients with pre-existingrespiratory disease. ¹² Appropriate counselling should therefore begiven to all patients with asthma who smoke and pharmacologicaltreatments such as nicotine replacement therapy may be relevant.

Patient involvement

Involving patients in their asthma managementplans, particularly those that include written advice for patientsto follow should symptoms and/or peak flow readings deteriorate,have been shown to reduce hospital admissions for asthma andare recommended in some current guidelines. ^{7, 8} How this can be applicable in our setting with low literacy rates remain to be determined.

Avoidance of allergen

The exposure of patients with atopic asthma to the allergensthat they are sensitive to has been shown to increase asthmasymptoms and airway hyper-responsiveness and to cause bronchoconstriction. Studies of allergen control measures in infancyhave shown reductions in respiratory symptoms, but it remainsto be determined if such measures will prevent the development ofatopy and asthma in adulthood. ¹³

Immunotherapy

Allergy specificity and reaction have been described in asthmatics, and its targeting in management may improve outcome. ¹⁴ Allergen specific immunotherapy, or desensitisation, involvesthe administration of specific allergen extracts via subcutaneousinjections of increasing concentration with the aim of inducingimmunological tolerance. The process may work by generatinginterleukin-10 producing regulatory T-cells. This has been found to be particularly useful in allergic rhinitis but has alsobeen shown to improve symptoms and airway responsiveness inpatients with allergic asthma. ¹⁵ Overall the benefits appearto be modest, but desensitisation therapy can be labour intensive, and is associated with life threatening anaphylaxis.

Pharmacological interventions

Most management guidelines have recommended graded interventions of therapy according to severity of symptoms and frequency of attacks. ^{7, 8}

Mild asthma

Evidence-based management here revolves around whether the asthma is mild intermittent or persistent. Mild intermittent asthmatics are those in whom symptoms occur less than once a week and have nocturnal symptoms ≤ 2 per month. Their peak expiratory flow rate (PEF) is ≥ 80% of predicted value and shows < 20% variability. They are asymptomatic and have normal PEF between attacks.  In mild intermittent asthma, the mainstay of therapy is still the use of Inhaled short acting ß₂-agonists which are shown to be effective in bronchodilation. ^{7, 8, 16} Their mechanism ofaction is thought to occur primarily by the relaxation of airwaysmooth muscle cells, but they also increase mucociliary clearance.They do not have any effective anti-inflammatory activity and should be used forsymptom relief when required. Their regular use provides no additional benefit andmay even be harmful. ¹⁶ The use of more than one canister of short acting ß₂-agonistsper month has been associated with poorly controlleddisease and should therefore alert the prescriber to the needfor increased regular anti-inflammatory treatment.

Mild persistent asthmatics are those in whom symptoms occur more than or equal to once a week but less than once a day. They have nocturnal symptoms more than twice a month while their PEF values are more than or equal to 80% of predicted value and show 20-30% variability. In this group corticosteroids are currently the most effective anti-inflammatoryagents for the treatment and inhaled corticosteroidsare currently recommended for all patients with persistent asthmawho require short acting ß₂-agonists more than onceper day or those with intermittent asthma who experience severeexacerbations. ^{7, 8} They exert their anti-inflammatory effects througha diverse range of mechanisms including the activation of theglucocorticoid receptors, leading to the regulation of transcriptionof target genes, and the direct inhibition of a range of inflammatorycells, particularly eosinophils. Studies have consistently shownthat treatment with regular inhaled corticosteroids resultsin significant improvements in airway inflammation in asthma.¹⁷There is also epidemiologicalevidence from cohort and case-control studies showing that regularlow dose inhaled corticosteroids reduce both hospital admissionsand asthma deaths. ¹⁸ A recent study of patients with mild, apparentlywell controlled asthma showed that the addition of regular lowdose inhaled corticosteroids resulted in significant reductionin asthma exacerbations compared with the control group. ¹⁹ These markedbenefits, coupled with the low incidence of side effects, haveled some to argue that inhaled corticosteroids should be givento all but the mildest patients. It is not yet fully known whetherlong term treatment with inhaled corticosteroids alters thenatural history of asthma, or protects against decline in lung function. Long term prospectivestudies of the effects of regular inhaled corticosteroids onthe decline in lung function in adults are needed to addressthis important issue.

In-addition, the cromones agents by inhalation, has been used as controller therapiesin mild persistent asthma. Though mechanism of action is notfully understood, they are believed to suppress IgE-mediatedinflammatory responses and may inhibit inflammatory cells. ²⁰ However, theyappear to be rather less effective than low dose inhaled corticosteroids and their long term effects on airway inflammation are unknown.The use of these agents in adults has therefore largely beensuperseded by the introduction of low doses of inhaled steroidsfor the majority of patients with persistent asthma. ²¹

Moderate Persistent Asthma

This refers to patients who use ß₂ agonist daily because of daily attacks and who have night time symptoms more than once a week. Their PEF values are more than 60% and less than 80% of predicted value and shows variability of more than 30%. Such patients may have been receiving treatment with lowdose inhaled corticosteroids and still have sufficient symptoms to justifya step up along the treatment ladder. There are an increasingnumber of treatment options for this group of patients. Long acting ß₂-agonists (e.g. salmeterol and formoterol)are currently generally recommended as the first choice forpatients who have symptoms that persist despite regular inhaledcorticosteroids. Salmeterol is a partial agonist of the ß₂-receptorswhile formoterol is a full agonist. Both appear to have similarclinical effects, but formoterol has a more rapid onset of action.Aswith short acting ß₂-agonists, these agents work primarilyvia the relaxation of airway smooth muscles, with additionaleffects on mast cells and vascular permeability, but withoutsignificant anti-inflammatory activity. This lack of anti-inflammatoryactivity precludes their use as first line agents in asthmaand current guidelines recommend that they are only prescribedalongside regular inhaled corticosteroids. ^{7, 8, 22} Long acting ß₂-agonists have been shown to improveday time and night time symptoms and reduce the need for rescue short acting ß2-agonists.In a randomised controlled trial of 852 patients treated withlow dose inhaled corticosteroids (the FACET study) the additionof formoterol to inhaled low or high dose budesonide improvedsymptoms and lung function and reduced the rate of acute exacerbations. ²³ In-addition, the OPTIMA study in patients with milder disease suggested thatthe addition of formoterol resulted in greater reductions inexacerbation frequency than doubling the dose of inhaled corticosteroids. ²⁴ One important concern with long acting ß₂-agonistsis that subjects recruited into many clinical trials are carefully selected and therefore notfully representative of the patients seen in everyday clinicalpractice.

The earlier approach to patients with persistent symptomsdespite low doses of inhaled corticosteroids was to increasethe corticosteroid dose, but the evidence for this is somewhatinconsistent. While some studies have demonstrated clear doserelated improvements in symptoms and lung function, ^{23, 25} others have not demonstrated clinically important benefits withmoderate or high doses. ²⁶ Overall the beneficial effects ofincreasing the dose of inhaled corticosteroids appear to bemodest and may be largely outweighed by the increased risk ofside effects.

The next group of agents are the leukotrienereceptor antagonists which are capable of markedly inhibiting exerciseinduced bronchoconstrictionand the various responsesto inhaled allergen.^27-29.Moreover, when added to as required short acting ß2-agonists,clinical trials have shown improvement in lung function. ³⁰ Clinical trials have also shown evidenceof efficacy in patients taking high doses of inhaled steroids, and the introduction of montelukast has been shown to allowa reduction in the dose of inhaled corticosteroid without lossof asthma control. ³¹ The effectiveness of the addition of leukotrieneantagonists compared with increasing the dose of inhaled corticosteroidsin patients with persistent symptoms, however, has not yet beenfully addressed.

In-addition, high up the ladder is theophylline which has been in use for many years as a bronchodilator, but due to adverse effects, it hasoften been reserved for use in patients with more severe asthma.Recent interesthas been in the use of theophylline at lower doses where therisk of side effects is minimised. The combination of low doseinhaled corticosteroids and theophylline has been shown to resultin comparable asthma control as higher doses of inhaled corticosteroidsand may provide slightly greater improvements in lung function. ³² Following a meta-analysis, long acting ß₂-agonistsare shown to be superior to theophylline in patients taking lowdoses of inhaled corticosteroids and result in fewer side effects as well. ³³ However, unlike long acting ß₂-agonists, theophyllinehas been shown to have anti-inflammatory activity andmay therefore be more beneficial in some patients.

Severe persistent asthma

This refers to patients with limited physical activity due to continuous symptoms. Night time symptoms are frequent and their PEF values are less than or equal to 60% of predicted values with a variability of more than 30%. This group of patients have persistent symptoms despiteappropriate treatment for moderate persistent asthma. It is imperative in this group of patients to ensure that the persistent symptoms are due to asthma rather than other aggravatingfactors such as rhinitis or gastro-oesophageal reflux and toassess compliance with existing therapy. Once these issues havebeen resolved, current guidelines recommend a step-up in treatment,usually with high doses of inhaled corticosteroids in combinationwith long acting ß₂-agonists, leukotriene antagonists,theophylline, oral ß₂-agonists, or a combination ofthese agents.^{7, 8} There have been no randomised controlled studiescomparing these different treatment options in this group ofpatients and therefore additional therapy should be institutedon a trial basis and discontinued if there is no objective evidenceof benefit. ³⁴

A further group of patients continue to have severe persistent asthma thatremains difficult to control despite the measures outlined above.In these circumstances treatment with oral corticosteroids,usually in the form of daily prednisolone, may be required tominimise symptoms and prevent severe asthma exacerbations. Whilecourses of oral corticosteroids are unquestionably a vital partof the management of acute exacerbations, careful considerationshould be made before they are administered on a long term basissince there is a high risk of significant adverse effects.When needed, the lowest dose which maintains asthmacontrol should be given. Prophylactic therapy for osteoporosisshould be considered and patients should be monitored for thedevelopment of hypertension, diabetes, cataracts, glaucoma,and adrenal suppression. Similarly, obesity, thinning and bruising of theskin, and myopathy are also important concerns. Other corticosteroid sparing agents that includemethotrexate, gold, and cyclosporine can be used in some instances. Although there is someevidence that these agents have steroid-sparing effects in asthmaeach has its own safety concerns and their use should belimited to specialist units. ^{35, 36}

There is also need for individualised treatment plans, required for different settings due to differences in circumstances regarding clinical presentation, and even in terms of personnel and resources. For instance, the severity of symptoms in asthma differs in pattern across the globe in epidemiology, risk profile and manifestations. ³⁷ Relevant guidelines have evolved to suit different settings even in some developing countries as South Africa. ³⁹

Future therapies

This involves the use of such agents as Anti-IgE monoclonal antibody. The hypersensitivity type 1 immunoglobulin, IgE has a significant role in the development of allergic diseasesin atopic subjects, and particularly asthma. ¹⁴ Its suppression is therefore a potentialtarget in the management of atopic asthma. A monoclonal anti-IgEantibody, omalizumab, which blocks the interaction of IgE withmast cells and basophils, has been developed. This agent given as subcutaneous injection at doses titratedto serum IgE levels, resulted in improved symptom control in a series of patients with resultantfewer exacerbations, and even a greater reduction in inhaled corticosteroiddoses with no apparent adverse effects. ⁴⁰ This is an important future treatment of patientswith atopic asthma.

The development of monoclonal antibodies to interleukin-5 has been widely acknowledged. This is based on the principle that the eosinophils are a characteristic inflammatory response cells in asthma. The inhibition of the cytokine interleukin-5, responsible for the maturation and release of this group of cells in the bone marrow represents another potentialtreatment. It has been shownthat the humanised anti-interleukin-5 monoclonal antibody SB-240563was able to reduce the sputum eosinophilia after allergen challengewhen given intravenously, though without effect on the early orlate fall in FEV₁, or on airway responsiveness. ⁴¹

More recently, the role of human recombinant interleukin-12 and interleukin-4 receptor antagonists in the armamentarium of management of asthma are being investigated.Interleukin-12 is a macrophage-derived cytokine that can suppress eosinophilicinflammation by modulating T-lymphocyte responses. In several studies it has been shown to suppress eosinophilic inflammationwith no associated improvements in airwayhyper-responsiveness. ⁴² It awaits further characterisation and development.

Interleukin-4 is another key cytokine in the development ofairway inflammation that has been targeted in the search fornovel asthma therapies by the use of its antagonists. Some initial reports have shown that this drug may reduce the deterioration in symptoms and the reduced lung functionthat follows after withdrawal of inhaled corticosteroids. ⁴³

Conclusion

Despite the recent advancement in understanding of the pathophysiology and targets for therapeutic interventions in asthma, the use of inhaled corticosteroids is still the cornerstone of treatment in chronic asthma. Steroids are effective in improvingeosinophilic airway inflammation, lung function and also controlasthma symptoms in most patients. But some patients will still require additionaltherapy. There is a range of effective additionaltreatments available.  It is vital to target treatmentsto patients who are most likely to respond through identification of individual treatment goals and careful assessment of likelyunderlying pathophysiology. In patients with more severe asthma,close monitoring of airway inflammation is required for optimalmanagement.

Currently, some novel therapeutic agents acting on specific componentsof the inflammatory pathways in asthma are emerging as discussed. The futuremanagement of asthma may well involve the useof these newer agents in combination with more established therapies, after their further development and establishment of efficacy. In another but equally important dimension, patient education and involvement is an essential component of successful asthma management. ⁴⁴ Current management approaches require patients and families to effectively carry on with complex pharmacologic regimens, institute environmental control strategies, detect and self-treat most asthma exacerbations, and communicate appropriately with health care providers. Doctors should train patients to gain the motivation, skill, and confidence to control their asthma. Research shows that asthma education can be cost-effective and can reduce morbidity for both adults and children, especially among the high-risk patients, with appropriate lifestyle intervention. ^{44, 45}

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