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Asthma: Treatment

Asthma: Treatment
should encompass assessment of severity and effica y of therapy, identification and removal of precipitating factors, therapy to reverse bronchoconstriction and inflammation patient and family participation and education. Diagnosis is determined on the basis of a characteristic pattern of signs and symptoms in the absence of alternative explanations.

Lung function: Primary assessment is with spirometry. Asthma is probable when inhaled bronchodilators cause more than 15% improvement in forced expiratory volume in 1 second (FEV1) or peak expiratory fl w rate (PEFR) (Chapter 20). The absence of improvement does not rule out asthma - the patient could be in remission and chronic severe asthma is poorly reversible. Airway resistance is least at midday and greatest at 3-4 a.m. Serial measurements of PEFR in the morning, mid- day and on retiring are useful for identifying the enhanced variation in airfl w limitation characteristic of asthma and for assessing response to therapy over time. Poorly controlled asthma shows a characteristic morning fall in PEFR (morning dipping). Occupational asthma is sug- gested when PEFR improves after a break from work. Lung function tests are often coupled with exercise tests in children, who often exhibit exercise-induced asthma.
Bronchial provocation tests can determine hyperresponsiveness (Chapter 24) when asthma is suspected but spirometry is not diagnostic. Patients inhale increasing doses of histamine or methacholine (acetylcholine analogue) until FEV1 declines by 20%. The dose at which this occurs (PD20FEV1) is greatly reduced in asthmatics, who are always hyperresponsive (Fig. 24b).
Skin prick tests identify extrinsic factors. Development of a wheal around the prick site indicates allergen sensitivity. Exposure to identifie allergens should be minimized (e.g. replacement of furnishings to reduce house dust mite, removal of pets). Only 50% of patients with occupational asthma are cured by avoidance of precipitating factors.
Asthma: Treatment

The goal is long-term control, and all patients except those with the mildest symptoms should receive anti-inflammator drugs as well as bronchodilators. International guidelines favour step-wise treatment regimens (Fig. 25a). Asthma therapy is centred on inhaled compounds (Fig. 25b), which maximize bronchial delivery while minimizing systemic side effects. Metered dose inhalers (MDI) are the commonest delivery system, although only approximately 15-20% of the dose may reach the lungs (Fig. 25c); this can be improved by use of spacers. Asthma drugs are often called relievers, bronchodilators that relieve acute symptoms, or preventers, prophylactic and anti-inflammator drugs that relieve chronic symptoms and hyperresponsiveness; some have both properties. Histamine antagonists have not proved useful in asthma.

Short-acting β2-adrenoceptor agonists (e.g. salbutamol) are rapid and powerful bronchodilators and are of firs choice for alleviating acute symptoms. They activate adenylate cyclase to increase cyclic adenosine monophosphate (cAMP). In addition to bronchodilation, they also reduce activation of mast cells. Long-acting β2-agonists (e.g. salmeterol) are used prophylactically, but must only be used for patients already on steroids (see below). Long-term use of β2-agonists is associated with reduced effectiveness (tolerance).

Corticosteroids (e.g. beclometasone) are the most important anti-inflammator (preventer) drugs, and suppress inflammator gene activation. Steroids reduce eosinophil numbers and activity of macrophages and lymphocytes. Inhaled steroids tay of long-term asthma therapy. However, they can have significan side ef- fects, including oral candidiasis (5%) and hoarseness. Growth may be retarded in children receiving high-dose inhaled corticosteroids. Oral corticosteroids such as prednisolone may be required in patients whose asthma cannot be controlled by inhaled steroids, but the danger of adverse effects is much greater. Combination therapies containing both steroid and long-acting β2-agonists are commonly used for moderate/severe asthmatics.

Muscarinic receptor antagonists (e.g. ipratropium) block the effects of acetylcholine from parasympathetic nerves to smooth muscle and mucus glands. They are moderately effective bronchodilators and reduce mucus secretion. They are slower and less effective than β2-agonists, and more useful against irritant than allergen-induced responses.

Xanthines such as theophylline have bronchodilatory and some anti-inflammator actions and are taken orally. They inhibit phosphodi-esterases that break down cAMP. Limitations include numerous side effects and a narrow therapeutic range; these are partially overcome by slow-release (SR) preparations. Xanthines are used as second-line drugs in asthma, particularly when β2-agonists are ineffective at controlling symptoms and in steroid-resistant asthma.

Antileukotriene therapy includes cysLT receptor (LTC4/D4) antagonists (e.g. montelukast) and 5-lipoxygenase inhibitors (e.g. zileuton). Both have equal eff cacy for bronchoconstriction caused by allergens, exercise and cold air. They are effective in aspirin-sensitive asthma, indicating the key role leukotrienes have in this condition (Chapter 24). Antileukotrienes improve lung function in mild and moderate asthmat- ics, but the greatest benefi may be for severe asthmatics taking steroids. Both drug types are taken orally and are relatively long-lasting, with few adverse effects.

Cromones (sodium cromoglicate, nedocromil) inhibit activation of mast cells and eosinophils, and may suppress sensory nerves and release of neuropeptides (Chapter 24). They are only effective prophylactically. Use has declined as they are less effective and more expensive than modern lowdose steroids, but are useful when steroids cannot be used. Allergen-specific immunotherapy: Recombinant anti-TgE anti-body (omalizumab) has been shown to be effective in moderate to severe allergic asthma, by reducing levels of antigen-specifi TgE. Promising results have been obtained in trials of anti-cytokine antibod- ies (e.g. anti-TL-13, anti-TL-5). Both require specialist treatment centres. Bronchial thermoplasty uses heat to reduce smooth muscle mass and function in medium airways, and has been used successfully in severe uncontrolled asthmatics.

Poorly controlled asthma is often related to poor compliance with treatment regimens-for example, due to peer pressure in children. Poor inhaler techniques are common. Compliance may also be poor when asthma is apparently controlled, so patients stop preventer therapies (e.g. steroids) because they are 'cured'. Patient education and training are therefore key to asthma therapy.

Severe uncontrolled asthma

Requires immediate treatment and hospitalization. Indications: inability to complete sentences ('telegraph speaking'), high respiratory rate, tachycardia, PEFR less than 50% predicted. Becomes life-threatening with one or more of: PEFR less than 33% predicted, hypoxaemia, hypercapnia, silent chest, exhaustion. Treatment: immediate nebulized β2-agonists +/- ipratropium delivered in oxygen and intravenous steroids, with subsequent oral steroids. Tn unresolving cases, intra- venous β2-agonists or xanthines and ventilation may be required.