Special Article

Bronchial Asthma : Recent Advances R. Kishore Kumar

North West Regional Hospital and University of Tasmania, Brickport Road, Burnie TAS 7320, Australia Abstract. Asthma is one of the oldest diseases about which there are lots of myths in most parts of the wodd. The exact cause of this global disease still eludes scientists. The recent knowledge about the pathogenesis of the disease, led to rationalise the medications into different groups. Parallel to the increasing incidence of this disease, is the knowledge about the trigger factors and steps to reduce their exposure. Childhood asthma is a lot different from asthma in adults, as many children won't be able to use the inhalers like adults and most children will not be able to do lung function tests until they are about 6 years of age. Unlike for any other diseases, research has helped year after year in developing new Strategies for management of asthma. Starting from definition of the disease to inventing newer medications, management of asthma has revolutionised in the last few years and has also accounted for the decreasing mortality in many countries. This article tdas to give an overview of bronchial asthma in children including recent advances and possible future developments. [Indian J Pedlatr 2000; 67(4) : 293-298]

Key words : Bronchial asthma; Inflammation; Leukotnenes. Asthma is one of the global problems which is on the rise since the last few years 1. Parallel to that is the knowledge and research into the understanding of the disease. The recent advances could be traced back into the year 1992, when a baseline definition of the disease 2 was agreed upon by all people concerned to replace terms like "allergic bronchitis", " h a p p y wheezer", "allergic airway disease" and "hyper-reactive airway disease". Despite this there is no universal acceptance of this definition and controversies continue to exist3. "Asthma is d e f i n e d as a chronic inflammatory disorder of the airways in which many cells play a role. In susceptible individuals this inflammation causes s y m p t o m s w h i c h are u s u a l l y a s s o c i a t e d with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment, and it also c a u s e s an a s s o c i a t e d increase in a i r w a y responsiveness to a variety of stimuli". (International consensus report on diagnosis and treatment of asthma, National Heart, Lung and Blood Institute, Bethesda, Maryland, USA2). The exact aetiology of this "global disorder" is still a mystery. Hence the abundance of the "theories". It is p r o p o s e d to be a d i s o r d e r i n v o l v i n g autonomic, Reprint requests : R. Kishore Kumar, Consultant Pediatrician and Lecturer in Pediatrics and Child Health, North West Regional Hospital and University of Tasmania, PO Box 258, Burnie TAS 7320, Australia. E-mail : R.Kumar@utas. edu.au Indian Journal of Pediatrics, 2000; 67 (4) : 293

immunologic, endocrine, infectious, genetic and psychological factors, in varying degrees in different individuals. (a) Autonomic : Control of the diameter of the airways is a balance of neural and humoral factors e.g., Cholinergic - bronchoconstriction; vasoactive intestinal peptide-bronchial smooth muscle relaxation; catecholamines-bronchial smooth muscle relaxation; histamine, leukotrienes - bronchoconstriction.

(b) Immunologic : In allergic or extrinsic asthma, exacerbations follow exposure to environmental factors like dust, pollens etc. These patients may have increased IgE. Intrinsic or infantile asthraa w h e t h e r early or late onset m a y not h a v e identifiable risk factors. (c) Infectious : Viral agents notably RSV are the most important triggers of asthma. Wheezing with bronchiolitis (RSV) is s u p p o s e d to unmask a predisposition to asthma. (d) Endocrine : Asthma is well known to worsen with puberty and in pregnancy. It also worsens with premenstrual syndrome.

(e) Genetic : It is most compatible with multifactorial inheritance. A child with one affected parent is at 25% risk of having asthma and the risk increases

R. Kishore Kumar

to about 50% if both p a r e n t s are asthmatic. H o w e v e r , it is not u n i v e r s a l l y p r e s e n t in monozygotic twins. (f) Psychological : Emotional factors can trigger symptoms in many asthmatics. These are thought to act through humoral factors. (g) Environmental : Recent issue and literature has abundant evidence about increasing incidence of asthma in industrialised nationsL The mechanism of mc~st of these "theories" is that there is underlying inflammation. Hence treatment is directed at reducing inflammation.

Pathogenesis Airflow obstruction in asthma is the result of (a) contraction of the a i r w a y s m o o t h muscle; (b) inflammation of the airways leading to mucus hypersecretion, m u c o s a l o e d e m a , i n f l a m m a t o r y cell infiltration and epithelial desquamation. The definition and pathogenesis leads us to come to an understanding of the rationale of the management of the disease on 2 broad principles : (a) Reliever medications (for relief of symptoms) e.g. salbutamol, terbutaline, ipratropium bromide. (b) P r e v e n t i v e m e d i c a t i o n s (for p r e v e n t i o n of s y m p t o m s ) e.g., s o d i u m c h r o m o g l y c a t e , nedochromil sodium budesonide, betamethasone, fluticasone propionate. If untreated, the inflammatory process in the long run can cause permanent changes in the airways.

Management of Chronic Asthma The goal of asthma management should be to allow children to be involved in normal activity, including full participation in exercise, sports, with minimal school absences; to prevent development of permanent damage to lungs and reduce the risk of death from an acute attack. This can only be done by minimising the symptoms, maximising and maintaining the lung function at its best at all times and identifying the trigger factors4-L This can only be achieved with a multi-modal approach : (a) Co-management~the partnership : It should be a combined management beween the family and 294

the physician. A single w a y m a n a g e m e n t is bound to fail. (b) Patient~parent education : The chronicity of the illness has to be informed to the family. This will a v o i d "the d o c t o r s h o p p i n g " a n d s e e k i n g alternative medicines for the management. This can be achieved by making them understand the condition, monitoring the symptoms, peak flow, and drug use by the patient/parents, having a prearranged action plan in case of exacerbations, w r i t t e n g u i d e l i n e s r e g a r d i n g the p l a n of management. (c) Environment control : Because asthma is a disorder involving environment as a potential cause, environmental control plays a significant step in controlling s y m p t o m s in children. Attention should be paid to cigarette smoking, food and other provocations (cat, pollen exposure), dust mite exposure etc. (d) Pharmacotherapy : For deciding on p h a r m a c o t h e r a p y three different patterns of cough/wheeze are recognised. First, infrequent episodic (less than monthly) patterns with one or t w o e p i s o d e s of w h e e z e a year, w i t h no intermittent symptoms like persistent nocturnal cough. These e p i s o d e s are m a n a g e d b y bronc'hodilator therapy as and when required. Daily preventive medications are not required in this group. Second, f r e q u e n t e p i s o d i c or persistent wheeze or persistent nocturnal cough, w h e r e these children s h o u l d be p r e s c r i b e d preventive medication. As a general rule, any child needing bronchodilator more than three times a w e e k will need p r e v e n t i v e therapy. P r e v e n t i v e m e d i c a t i o n s can be either nonsteroidal anti-inflammatory drugs (NSAID) like sodium chromoglycate or nedochromil sodium or inhaled steroidal anti-inflammatory drugs like beclomethasone, b u d e s o n i d e or fluticasone dispropionate. It a child has mild to moderate s y m p t o m s as d e s c r i b e d a b o v e , s o d i u m chromoglycate or nedochromil sodium-two puffs three times a day by a spacer and mask should be the drug of first choice. About 70% of children w i t h mild to m o d e r a t e a s t h m a r e s p o n d to NSAIDs. Third pattern is seen with no response to the a b o v e t r e a t m e n t for 4 to 6 w e e k s , or w i t h Indian Journal of Pediatrics, 2000; 67 (4)

Bronchial Asthma : Recent Advances

m o d e r a t e to severe s y m p t o m s like n e e d i n g hospitalisation for acute severe asthma. They should receive a therapeutic trial of an inhaled steroid by a spacer and mask. As soon as inhaled steroids are commenced, the NSAID should be stopped. The initial dose recommended is 100 to 200 mcg twice daily, which could be increased upto 800 mcg twice a day. But at a dose of 2000 mcg, the therapeutic efficacy curve becomes flattened suggesting that further increments in doses are not accompanied by any clinical benefit. Generally, fluticasone is reserved for children needing high doses of inhaled steroids (>800 mcg twice a day) because of high potency and cost.

Theophyllines have become second line drugs due to their toxic side effects. Long acting beta agonists like s a l m e t e r o l a n d e f o r m e t e r o l (symptom controllers) are used in conjunction with preventers, if there are persistent symptoms, but they should never be used alone. Using a spacer a n d m a s k r e d u c e s o r o p h a r y n g e a l deposition and therefore, the risk of systemic side effects and topical side effects such as oral thrush and dysphonia. At any stage if a child fails to r e s p o n d to treatment, one has to check the technique of the use of inhalers and spacers along with compliance. (e) Inhalation or delivery systems (Tables 1 & 2) : The invention of spacers has revolutionised the management of asthma in children~;~'.9.1~Spacers have largely replaced the need for nebulisers in most cases of asthma management. Nebulisers are expensive, bulky to carry, time consuming, need electrical supply, are noisy and tolerated poorly by m a n y infants because of the noise. Spacers offe~ the following advantages 11,12.

TABLE1 : Inhalational Devices for Different Age Groups Age (years)

Inhalation Delivery System

<2

Nebuliser and air compressor or spacer and face mask

2 to4

Metered dose inhaler with a spacer (with or without a valve) (a) Breath-a-tech or Aerochamber (small volume spacers) (b) Volumatic (Alien and Hanburys) (c) Nebuhaler (Astra) (d) FISONair (Fisons) and/or Nebuliser

5 to8

>8

Power inhalers (a) Spinhaler (Fisons) (b) Diskhaler and Rotahaler (Glaxo) (c) Turbohaler (Astra) (d) Metered dose inhaler with valved spacer and/or nebuliser

9

Decrease the p r o b l e m of p o o r i n h a l e r technique with Metered Dose Inhaler (MDI).

9

Eliminate, largely, oral absorption of inhaled corticosteroids.

9

Are,,as effective as nebuliser in the treatment of acute asthma.

9

Allow the aerosols to d e c e l e r a t e a n d propellents to e v a p o r a t e from the d r u g particles.

Autohaler (3M) or Metered dose inhaler TABLE2. Types of Spacers

Small spacers

Large spacers

1. Capacity around 150 rnls

1.

Volume around 750 mls.

2. No expiratory valve

2.

Expiratory valve present.

3. Lessintimidating to infants

3.

No drug dose variation as compared to aerochamber.

4. Easierto handle when trying to hold a wriggling infant.

4.

Valves open and close at low flow generated by infants. But partially open valve is likely to significantly impair the drug delivery.

5. Variation in dose delivered is more compared to nebuhaler with aerochamber Examples : Breath-O-Tech,Aerochamber and Coffee cup

Indian Journal of Pediatrics, 2000; 67 (4)

Examples : Nebuhaler (Astra), Volumatic (Glax0) and Fison Air (Fison).

295

R. Kishore Kumar

9

Cost of the treatment is less (no need for nebs/less puffs from MDIs)

The disadvantages of spacers are : 9

Efficacy of a particular spacer with one drug cannot be assumed for another drug.

9

Static electricity m a y decrease the d r u g particles available.

9

Multiple actuations of MDI into spacer before inhalation may decrease the proportion of the drug inhaled.

9

Delay between pressing the MDI "puff" into the spacer and inhalation may decrease the amount of drug available for inhalation.

9

Newer formulations in which hydrofluroalkanes replacing older propellents may behave very differently in spacers. (New study in press : double potent than of a conventional MDI)

To achieve best results with spacers, it should be prescribed with the following advice : 9

I n t r o d u c e the d r u g into the spacer by repeated single accentuations of MDI, each followed by atleast 4 inhalations.

9

Keep the d e l a y to a m i n i m u m b e t w e e n actuation of MDI and inhalation from the spacer.

5-10 inhibitors ~ Ex : Zileuton

Arachidorucacid uPoxygenease

x

.

LTB4 }

I Chemota

~

Immunomodulalioni

I LTA4

t

LTantagonists

Ex : Pranlukast and Zatirlukast

~/

..~ LTE,J | | |

Bronchoconstriction ] Mucussecretion Oedema Hyperresponsivenoss Eosinophilia

Fig. 1. New class of anti-asthma drugs directed against LT synthesis and activity.

296

9

Decrease the static electricity by washing it in soap and drying in air atleast twice a month.

(f) Immunotherapy : There are considerable variations in attitudes to this treatment and controversies will only be resolved w h e n larger and more carefully controlled studies are performed 13. It should h o w e v e r be used only w h e n a clear unavoidable allergic trigger has been identified. It appears to be most beneficial in patients with seasonal asthma and rhino-conjunctivitis.

(g) Other drugs :

Ketotifen has been shown to be of benefit in mild asthma mainly in infancy. Frusemide has varying results. Controlled studies have not established their efficacy.

Magnesium sulphate a known pulmonary vasodilator, has been used in acute severe asthmatics with a view to avoid ventilation, with varying results. (h) Stress : Yoga, hypnosis and psychotherapy help to reduce the stress and this in turn has helped reduce the exacerbations in children specially in those w i t h p s y c h o l o g i c a l p r o b l e m s as the precipitating cause for multiple exacerbations. (i) AltePnative treatments : Many families rely on herbal and n u t r i t i o n a l t h e r a p i e s out of desperation or some other reason. Traditional Chinese herbal r e m e d i e s like e p h e d r a (Ma huang), Chinese skullcap, angelica (Dong quai), licorice root - are known to be rich in adrenaline; which is a well k n o w n reliever for centuries. Vitamin and mineral supplements like Vitamin B6 (pyridoxine), vitamin C, magnesium, fish oils have been used with no proven benefits. Onions, spicy foods, caffeine, avoidance of milk and milk products-have some anecdotal evidence, but have not been proven effective in trials. Acupuncture and h o m o e o p a t h y haven't s h o w n consistent results. Recent Advances in the Management of Asthma Recent advances in the m a n a g e m e n t of asthma in children have brought a wide array of medications into the arsenal of the practising peadiatrician. These include Indian Journal of Pediatrics, 2000; 67 (4)

Bronchial Asthma : Recent Advances

long acting ~2 agonists like salmeterol and eformoterol, which have added to the control of asthma in children. These have been labelled as symptom controllers and their role is very specific - to achieve control of symptoms in those children who are already on high dose inhaled steroids (more than 1000 mcg of inhaled steroids). The i n t e r n a t i o n a l regulations, r e g a r d i n g the protection of our ozone l a y e r m e a n s that all the countries in the world will have to say good bye to all the CFC propellent inhalers in the next 2 to 3 years. The new "CFC free" inhalers which are being released into the market (e.g., aromir) to replace the current inhalers may be more potent than the ones we have been using (Unpublished data). The new class of inhalers like aerolisers, accuhalers and turbuhalers are all efforts of the various drug companies in this regard to replace the existing ones. The knowledge that the products of lymphocytes like i n t e r l e u k i n s a n d l e u k o t r i e n e s m a y r e g u l a t e the inflammatory activity of eosinophils and mast cells within the asthmatic l u n g and m e d i a t e bronchoconstriction", led to the discovery of the new class of drugs called leukotriene antagonists and leukotriene inhibitors'L Leukotrienes (LTs) are metabolites of the f a t t y acid a r a c h i d o n i c acid. A r a c h i d o n i c acid is p r e s e n t e d to the 5-1ipoxygenase e n z y m e by 5lipoxygenase-activating protein (LAP), a cofactor in the nuclear membrane, and their interaction leads to the formation of an unstable intermediate LTA4. Depending on the cell type, further conversion of LTA4 may occur to chemotaxin LTB4; or to cysteine containing LTC4. Further conversion of LTC4 to LTD4 and then to LTE4

occurs by the actions of enzymes ubiquitous in the tissues and circulation ~6(Fig. 1). Four classes of drugs are c u r r e n t l y u n d e r trial as a n t i - a s t h m a or antiinflammatory drugs, which interfere with LT synthesis or activity. They can be b r o a d l y categorised into leukotriene inhibitors and leukotriene antagonists. Zileuton, a leukotriene inhibitor and pranlukast and Zafirlukast - two leukotriene antagonists have already shown promising results in the field trials in parts of USA and Japan. They have been shown to increase FEV 1, increase the morning pEFR, improve both day - and night time symptoms, decrease ~-agonist use, improve exercise tolerance and decrease the dose needed for control of symptoms of inhaled steroids. Currently they are under multicenter trials all over the world with promising results 17,~8.The advantage of these medications is that they are available as oral tablets and need to be taken once or twice a day, avoiding the need for all these inhalers and spacers, which means soon we may be able to say good bye to all that we have leamt so far! Future o f A s t h m a

A lot of media attention has been given to this global problem in the last few years, including the possibility of a new vaccine against asthma. In his discussion on this topic Hall 19mentions about the possible future developments that can take place in the field of asthma. These inclu~le genetic screening for 'at risk' individuals, targeted gene therapy, new therapeutic agents and possible immunisation approaches such as anti-IgE antibodies.

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12. British Thoracic Society. British Guidelines on Asthma management 1995. Review and Position statement. Thorax 1997; 52 (Supp 1) : S1-$21. 13. Kon OM, Barnes N. Immunosuppressive treatment in asthma. BrJ Hosp Med 1997; 57 (8) : 383-386. 14. Samuelsson B. Leukotrienes : mediators of immediate hypersensitivity reactions and inflammation. Science 1983; 220 : 568-575. 15. Chanarin N, Johnston SL. Leukotrienes as a target in asthma therapy. Drugs 1994; 47 : 12-24. 16. Sampson AP, Casting DP, Green CP, Price JF. Persistent

increase in plasma and urinary leukotrienes after acute asthma. Arch Dis Child 1995; 73 : 221-225. 17. Virchow ]C, Nolle PS, Wiessman KJ et al. Multicenter trial of Bay x 1 0 0 5 , a new 5-1ipoxygenase activating protein inhibitor in the treatment of chronic asthma. Am J Respir Crit CareMed 1995; 151:377. 18. Hui KP, Barnes NC. Lung function improvement in asthma with a cysteinyl leukotriene antagonist. Lancet 1991; 337 : 1062-1063. 19. Hall IP. The future of asthma. BMJ 1997; 314 : 4549.

ANTIMICROBIAL RESISTANCE AND ITS CONTROL Factors associated with antimicrobial resistance include: 1. Increased antimicrobial use in the community and in hospitals i.e. increase in empiric antibiotics, prolonged and broad-spectrum antibiotic courses and repeated antibiotic courses. 2. Prolonged hospitalizations 3. Prolonged stay in intensive-care units 4. Severely ill patient status 5. Immunocompromised state 6. Increased use of invasive devices and catheters 7. Ineffective infection control procedures 8. Interhospital transfers of colonized patients 9. Antibiotic use in animal husbandry and agriculture 10. International travel Principles to control antimicrobial resistance include : 1. Appropriate antimicrobial use i.e. optimal use of antimicrobial agents-whether therapeutic, prophylactic, or empiric; restriction of certain antimicrobial agents; rotation of antimicrobial agents used; combination antimicrobial therapy; implementation of guidelines for common antibiotic use 2. Antimicrobial resistance surveillance programs i.e. prompt detection and reporting of new resistance patterns; rapid detection of resistant microorganisms 3. Aggressive infection control programs in hospitals i.e. prompt identification and isolation of patients colonized with resistant strains or organisms 4. Physician and paramedical staff education 5. Computer-based monitoring and feedback of use of antimicrobial agents 6. Multidisciplinary approach in controlling antimicrobial resistance 7. Professional review of hospitals by oversight agencies such as the Joint Commission on Accreditation of Healthcare Organisations

Abstracted from: Mayo Clin Proc Feb 2000; 75:205-210 298

Indian Journal of Pediatrics, 20,00; 67 (4)