Asthma

Bronchial asthma.(atopic asthma) / (status asthmaticus).

Definition

Bronchial asthma is a chronic inflammatory disease of the airways characterised by an increased responsiveness of the tracheobronchial tree to a variety of stimuli. It is manifested as paroxysms of dyspnoea, cough and wheezing,

resulting from narrowing of the airways by a combination of muscle spasm, mucosal oedema and viscid bronchial secretion. The airflow limitation is generally reversible spontaneously or with treatment.

Classification

Bronchial asthma can be classified into two broad groups:

1.Early onset asthma (atopic, allergic, extrinsic).

2.Late onset asthma (non-atopic, idiosyncratic, intrinsic).

Features

Early onset (atopic) asthma

Early age of onset

Atopic individuals

External allergens have strong role

Positive personal and/or family history of allergic diseases like rhinitis, urticaria and eczema

Increased levels of IgE in the serum

Positive skin hypersensitivity tests

Positive response to provocation tests.

Late onset (non-atopic) asthma

Late age of onset

Non-atopic individuals

External allergens have no role

Negative personal and/or family history of allergic diseases

Normal levels of IgE in the serum

Negative skin hypersensitivity tests

Negative response to provocation tests

Note that this classification is broad and by no means are the features described absolute. In fact, a great degree of overlap exists between these two types.

Aetiopathogenesis

Pathogenesis of asthma involves two major factors:

1.Bronchial hyper-responsiveness.

2.Inflammatory reaction within bronchial wall.

Role of allergens

The allergens responsible for asthma enter the body through various routes:

Inspired air (house dust, pollen, feather, animal dander, fungal spores, etc.).

Ingestion (allergens in fish, egg, milk, yeast and wheat).

Previous exposures to these allergens will have stimulated the formation of IgE. Hence, subsequent exposure to these specific allergens will result in an anaphylactic antigen-antibody reaction in the bronchi. This causes the release of pharmacologically active substances from cells in the bronchial wall, which provoke bronchial constriction and inflammatory reaction, leading to symptoms.

Pathogenesis

Pathogenesis of asthma is complex and is not fully understood. It involves a number of cells, mediators, nerves and vascular leakage. The airway inflammation is a chronic inflammation driven by CD4+ cells which leads to IgE synthesis through production of interleukin-4 (IL-4) and eosinophilic inflammation through IL-5.

Mast cells are increased in both respiratory epithelium and surface secretions of asthmatics. These cells can generate and release powerful mediators acting on smooth muscles and blood vessels. These mediators include histamine, prostaglandin D2 (PGD2) and leucotriene C4 (LTC) which cause the immediate asthmatic reaction.

Eosinophils release LTC4 and basic proteins such as major basic protein, eosinophilic cationic protein and peroxidase that are toxic to epithelial cells.

Macrophages play a role in the initial uptake and presentation of allergens to lymphocytes. They release prostaglandins, thrornboxane, LTC4, LTB4 and platelet activating factor (PAF).

Lymphocytes release IL-3, IL-4 and IL-9 which activate mast cells. They also release IL-3, IL-5 and other factors

which activate eosinophils. Secretion of IL-4 helps in switching of antibody production by B cells to IgE type.

All these mediators lead to inflammation, oedema, hypertrophy of mucus-producing glands and bronchial constriction. o A summary of cells and mediators involved in the pathogenesis of asthma and some of the trigger factors is shown in

the following boxes:

Cells involved in the release of mediators

Important Less important

Mast cells • Neutrophils

Macrophages

Platelets

Eosinophils

Epithelial cells

Lymphocytes

Symptoms

Clinical features

Clinical features are conveniently discussed under three headings:

1.Episodic asthma.

2.Severe acute asthma (status asthmaticus).

3.Chronic asthma.

In general, atopic individuals develop episodic asthma and non-atopic individuals develop chronic asthma.

Episodic asthma

Occurs as episodes with asymptomatic intervening periods.

Characterised by paroxysms of wheeze and dyspnoea with relatively sudden onset.

Episodes may be spontaneous in onset or triggered by allergens, exercise or viral infections.

Attacks may be mild or severe and may last for hours, days or even weeks.

Severe acute asthma (status asthmaticus)

It is a condition in which severe airway obstruction and asthmatic symptoms persist despite the initial administration of standard acute asthma therapy.

Severe dyspnoea and unproductive cough.

Patient adopts an upright position fixing the shoulder girdle to assist the accessory muscles of respiration.

Physical signs include sweating, central cyanosis, tachycardia and pulsus paradoxus.

Chronic asthma

Symptoms are usually chronic unless controlled by appropriate therapy.

Symptoms like chest tightness, wheeze, and breathlessness occur on exertion.

Episodes of spontaneous cough and wheeze occur during the night.

Repeated attacks of 'severe acute asthma' are common.

Chronic cough with mucoid sputum, punctuated by recurrent attacks of purulent expectoration from frank infection,

is a common feature of chronic asthma. At times, it becomes difficult to distinguish it from chronic bronchitis.

Physical signs in the chest

During an attack of asthma, the following signs are detectable:

Respiratory rate is increased with the use of accessory muscles of respiration.

Hyper-resonant percussion note over the lungs.

Breath sounds are vesicular in character with prolonged respiration.

Numerous high pitched polyphonic expiratory and inspiratory rhonchi are audible.

During very severe attacks, the airflow may be insufficient to produce rhonchi. This results in a 'silent chest' which is an ominous sign.

In between the attacks, the chest is clear and no abnormal physical signs may be detectable.

Chronic asthmatics usually have some scattered rhonchi always persisting in their chest.

Investigations

Chest radiography:

In an acute attack, lungs appear hyperinflated.

In between attacks, lungs look normal.

Long-standing cases have hyperinflated lungs indistinguishable from emphysema.

Complications like pigeon chest, lobar or segmental collapse, pneumothorax, and mediastinal and subcutaneous emphysema may be seen.

Pulmonary function tests useful in bronchial asthma are forced expiratory volume in one second (FEV1), vital capacity (VC) and peak expiratory flow rate (PEF). They are of use in certain situations:

Estimation of the degree of airflow obstruction.

To determine whether and to what extent the airflow obstruction can be relieved by bronchodilators and corticosteroids.

To confirm airflow obstruction provoked by exercise, hyperventilation and occupational exposure.

To differentiate chronic asthma from chronic bronchitis. In asthma, there is a diurnal variation in PEP, the lowest values being recorded in the mornings ('morning dipping').

Long-term monitoring of patients with poorly controlled disease.

Asthma can also be diagnosed on the basis of demonstrating a greater than 15% improvement in FEVI (or PEP)

following the inhalation of a bronchodilator. However, this degree of response may not be present in all cases.

Histamine or methacholine provocation test (fall in FEVI by more than 20% after provocation with these agents) indicates the presence of airway hyper-responsiveness and can be useful in the patients in whom cough is the only symptom.

Arterial blood-gas analysis shows hypoxia and hypocarbia. In severe acute asthma, hypercarbia develops.

Skin hypersensitivity tests check the development of a wheal-and-flare reaction to intradermal injections of common allergens. The chief value of this is to distinguish atopic from non-atopic subjects (though even this differentiation is not required for management).

Sputum and blood eosinophilia.

Elevated serum IgE levels.

Management of bronchial asthma

Management of bronchial asthma can be discussed under three broad headings:

1.Avoidance of allergens.

2.Desensitisation or immunotherapy.

3.Drug therapy to control or suppress clinical manifestations.

Avoidance of allergens

In cases where a single allergen is found responsible, it is easy to reduce or avoid the exposure to it.

In cases where multiple allergens are found responsible, avoidance becomes a difficult task.

Desensitisation or itntnunotherapy

Desensitisation is done by repeated subcutaneous injections of gradually increasing doses of the extracts of allergen(s). Its value is doubtful.

Drug therapy

The drugs useful in asthma can be grouped into seven major categories. Often, a single drug may not be adequate when a combination of drugs is required:

1.Beta-adrenoreceptor agonists.

2.Methyl xanthines.

3.Corticosteroids.

4.Chromones.

5.Anticholinergics.

6.Leucotriene inhibitors.

7.Miscellaneous agents.

Beta-adrenoreceptor agonists

Basically, there are two types of beta-adrenoreceptors: betai-adrenoreceptors and beta2-adrenoreceptors.

Stimulation of betai-adrenoreceptors produces predominant effects on heart.

Stimulation of beta2-adrenoreceptors produces predominant effects on bronchial smooth muscles.

Catecholamines

The useful catecholamines are adrenaline, isoprenaline and isoetharine. Adrenaline is the most commonly used agent in this group. However, it has the disadvantage of not being beta2-selective, which results in significant undesirable cardiovascular side effects. The usual dose is 0.3-0.5 mL of a 1:1000 solution administered subcutaneously which may be repeated thrice at an interval of 20 minutes. It is useful in children.

Salbutamol, levosalbutamol, terbutaline, fenoterol

These drugs are highly selective for beta2-adrenoreceptors with their predominant action on the respiratory tract. They are powerful and rapidly but short-acting bronchodilators, which act by relaxing bronchial smooth muscles. They are active by all routes of administration (inhalation, oral, intravenous, subcutaneous), but the preferred route of administration is inhalation. Inhalation is extremely effective, since it rapidly reduces airflow obstruction. Intravenous administration of salbutamol and terbutaline offers no advantages over inhalation. For the same reason, other routes of administration are preferably avoided and reserved for selected indications. Levosalbutamol produces less tachycardia compared to salbutamol.

For inhalational route, these are available as solutions (for nebulisation), aerosol (metered dose inhaler or MDI) and dry powder inhaler (DPI).

Dose:

Salbutamol is given in a dose of 2-4 mg thrice a day orally or two puffs of 100 i.tg each as required.

Terbutaline is given in a dose of 2.5-5 mg thrice a day or two puffs of 100 i.tg each as required.

Levosalbutamol is given in a dose of two puffs of 50 i.tg each as required.

Main side effects are tremor and palpitation. Prolonged use of these beta2-adrenoreceptor agonists are preferably avoided as they worsen bronchial hyper-responsiveness.

Bambuterol - It is a long acting beta2-adrenoceptor agent which can be given orally in a dose of 10-20 mg once in a day

Salmeterol and formoterol

These are highly selective, potent and long-acting [32-stimulants that need to be given once or twice a day by inhalation (either as aerosol or dry powder).

These drugs are now routinely used in place of short-acting [32-stimu1ants when the patient requires regular I2-stimulant therapy.

Salmeterol has a slow onset of action while formoterol has a rapid action.

Dose:

Salmeterol—two puffs of 25 i.tg each two to three times a day.

Formoterol—two puffs of 6 i.tg each one to three times a day.

Methyl xanthines

Theophylline

Theophylline is a medium potency bronchodilator, the exact mechanism of bronchodilatation being not clear. It improves the movement of airway mucus and decreases the release of mediators.

Theophylline derivatives can be given intravenously, orally or as suppository. Therapeutic plasma concentrations of theophylline lie between 10 and 20 i.tg/mL. However the dose required to achieve this level varies from patient to patient.

Acute attacks are treated with short-acting theophylline preparations. For maintenance therapy, long-acting theophylline preparations are used, and are usually given once or twice a day. Single daily dose in the evening is effective in controlling nocturnal asthma.

Usual dose is 100-200 mg (of plain preparation) three times a day, and 300 mg twice a day or 450-600 mg once a day for sustained-release preparation.

Common side effects of theophylline preparations include nervousness, nausea, vomiting, anorexia and headache. Seizures and cardiac arrhythmias can occur when plasma levels are more than 30 lig/mL.

Theophylline (and aminophylline) clearance is reduced in elderly, liver disease, congestive heart failure, and with concurrent use of erythromycin, allopurinol and cimetidine. It is increased with concurrent use of phenytoin and phenobarbitone, and in smokers.

Aminophylline

Aminophylline is a bronchodilator, which is effective orally, intravenously and as a suppository. The preferred route of administration is intravenous. Intravenous aminophylline therapy may have some role in the management of status asthmaticus (severe acute asthma).

Aminophylline is given as a loading dose of 5 mg/kg slowly intravenously over 20 minutes. This is followed by a maintenance dose of 0.5 mg/kg/hour, given as a continuous intravenous infusion. In those patients already receiving theophylline, loading dose is preferably withheld or in extreme situations given in a reduced amount at 0.5 mg/kg.

Rapid infusion of the bolus dose can result in sudden death from cardiac arrhythmias. Additional side effects are headache, palpitation, dizziness, nausea, hypotension and precordial pain. When the plasma concentration exceeds 201.1g/mL, tachycardia, restlessness, agitation, vomiting and seizures can occur.

Doxophylline (doxofylline)

A new methylxanthine-derivative.

Like theophyline, it also inhibits phosphodiesterase leading to increased cyclic 3',5 '-adenosine monophosphate (cAMP). It has reduced affinity for adenosine Al and A2 receptors and therefore, has a better safety profile compared to theophylline. It also inhibits platelet-activating factor-induced bronchoconstriction and subsequent generation of thromboxane A2.

Dose is 400 mg twice a day.

Corticosteroids

Corticosteroids are not bronchodilators, but they relieve or prevent airflow obstruction indirectly by their anti-inflammatory

effect. They have a beneficial effect on bronchial inflammation and decrease bronchial hyper-responsiveness.

The effects of corticosteroids in acute asthma are not immediate and may not be seen for 6 hours or more after the first

dose. Consequently, it is mandatory to continue vigorous bronchodilator and oxygen therapy during this period.

The vast majority of patients respond to corticosteroids. But there is a minority with little or no response to corticosteroids. They have been labelled corticosteroid-resistant cases.

Common indications of corticosteroids in bronchial asthma are the following:

Acute illness, particularly when not responding to or even worsening despite optimal bronchodilator therapy.

Severe acute asthma (status asthmaticus).

Corticosteroid inhalers are now the first line of treatment in all patients who require some anti-asthmatic drug regularly. This is because they have their main action on the basic pathophysiology, i.e. they reduce the hyper-responsiveness and inflammation of the bronchial tree.

Hydrocortisone and methylprednisolone (intravenous) are useful in acute situations. Hydrocortisone is given as a loading dose of 4 mg/kg intravenously followed by 2-3 mg every 6 hours. Methylprednisolone is administered in a dose of 40-125 mg every 6 hours.

Prednisolone is started as a single daily morning dose of 40-60 mg orally. Thereafter the dose is reduced by half every

third to fifth day. An alternate day schedule is preferred where steroid therapy has to be continued for a long time.

Beclomethasone dipropionate (200 jig), budesonide (200 lig) or fluticasone (125 lig) is given twice daily as aerosols or dry-powder form. Another inhalational steroid is ciclesonide which is given in a dose of 80-160 jig once a day. Higher doses may be necessary in severe illness, but not beyond the maximum dose of 1500 lig beclomethasone or fluticasone per day and 2000 lig budesonide per day. They are relatively free from systemic side effects at the conventional doses. The common side effects are oropharyngeal candidiasis and a husky voice. This can be minimised by the use of a spacing device along with the metered-dose inhaler, and gargling with water after use.

Chromones

Sodium cromoglycate or cromolyn is not a bronchodilator. It inhibits the degranulation of mast cells, thereby preventing mediator release. It is only of use in the prophylactic treatment of asthma. Sodium cromoglycate is particularly useful in children with atopic asthma, but may be of some value in a few patients with non-atopic asthma.

Therapy is best initiated between attacks or in periods of relative remission. If no response is observed in 4-6 weeks, the drug can be discontinued. Sodium cromoglycate is administered as an inhalation.

Nedocromil sodium acts mainly by inhibiting release of mediators. It is given as an inhalation at a dose of 4 mg two to four times daily. It is of use in the prophylactic control of asthma.

Ketotifen is not a chromone. It is an antihistaminic that also inhibits release of mediators. It is useful in the prophylactic control of asthma at a dose of 1-2 mg twice daily by mouth. The main side effects are drowsiness and weight gain. Anticholinergics

Previously, anticholinergics like atropine sulphate and atropine methylnitrate were used but their role is limited by the systemic side effects. The agents currently used are ipratropium bromide and tiotropium. These are non-absorbable quaternary ammonium compounds, relatively free from side effects. These are given as aerosol or in dry-powder form. These agents are particularly useful in two situations:

1.In patients with co-existent heart disease, in whom methyl xanthines and beta2-adrenoreceptor agonists produce significant tachycardia.

2.In refractory cases, addition of ipratropium bromide or tiotropium enhances the bronchodilator action of beta2-adrenoreceptor agonists.

Dose:

Ipratropium two puffs of 20 [is each four times a day.

Tiotropium two puffs of 9 lag each once a day.

Leucotriene inhibitors

Leucotriene receptor antagonists (montelukast, zafirlukast) and 5-lipoxygenase inhibitors (zileuton) are useful additive drugs in patients who do not respond to the conventional agents. They are also used in patients who require high doses of inhaled steroids.

Dose of zafirlukast is 20 mg BID.

Dose of montelukast is 10 mg once a day in the evening.

Miscellaneous agents

Steroid-dependent patients might benefit from the use of immunosuppressants like methotrexate or gold but their exact role has not been defined.

Omalizumab, a recombinant humanised monoclonal antibody against IgE has been shown to be useful in patients with allergic asthma.

Note:

Avoid opiates, sedatives and tranquillisers in acutely ill asthmatics.

Avoid beta-blockers and parasympathetic agonists in asthmatics.

Expectorants and mucolytic agents do not have any significant role in the management of bronchial asthma.

Use of an inhaler

1.The canister of inhaler is shaken well.

2.The patient exhales till functional residual capacity, i.e. the end of normal expiration.

3.The nozzle of inhaler is kept near the open mouth; it may also be kept inside the mouth.

4.The patient activates the inhaler by pressing it and simultaneously inhales rapidly but smoothly till full inspiration.

5.The breath is held for 10 seconds, and then released.

6.The patient rinses his mouth with plain water.

7.The same steps are repeated after 2-5 minutes if the inhaler needs to be taken twice.

Spacer

The spacer is conical in shape and is made of plastic or other materials.

One end of this is attached to the inhaler (after the inhaler has been shaken) and the other end is kept in the mouth.

The patient inhales after activating the inhaler.

Spacers reduce the particle velocity so that less drug is deposited in the mouth; this increases the delivery of drug to the lower

airway passages and also reduces the side effects (spacers are quite useful in reducing local side effects of steroids).

Spacers also diminish the need of coordination between the activation of inhaler and inhalation.

Treatment of exercise-induced asthma

Episodes can be prevented by the inhalation of 2 metered doses of salbutamol or terbutaline a few minutes before exercise.

If beta2-adrenoreceptor agonists are not effective, regular treatment with sodium cromoglycate or an inhaled corticosteroid may be necessary.

Treatment of severe acute asthma (status asthmaticus)

Treatment at home

High concentrations of oxygen through an MC mask.

Bronchodilator therapy with one of the following:

Salbutamol (5 mg) or terbutaline (10 mg) by nebuliser every 20 minutes for 3 doses.

Salbutamol or terbutaline administered via metered-dose inhalers (four to eight puffs with a spacer every 20 minutes for three doses) has been found to be as efficacious as nebulisation of these agents.

Salbutamol (250 fig) or terbutaline (250-500 i.tg) as slow intravenous injection.

Aminophylline 5 mg/kg intravenously over 20 minutes in those who are not already on methyl xanthines.

Corticosteroid therapy with one of the following:

Hydrocortisone sodium succinate 200 mg intravenously.

Methylprednisolone 125 mg intravenously.

Prednisolone 40-60 mg orally.

Treatment in hospital

High concentration of oxygen (35-60%).

Salbutamol (5 mg) or terbutaline (10 mg) nebulised in oxygen should be administered immediately. This may be repeated after a few minutes if there is no response.

Subcutaneous or intravenous administration of P2-agonist is indicated in patients who are coughing excessively, too weak to inspire adequately or moribund. Terbutaline is given subcutaneously (0.25-0.5 mg) or intravenously (0.1-10 lig/kg/minute). Epinephrine (adrenaline) may be given in children and young adults. In adults, the dose is 0.2_0.5 mg as 1:1000 solution subcutaneously every 20 minutes.

Ipratropium bromide 0.5 mg together with salbutamol 5 mg or terbutaline 10 mg nebulised in oxygen in those patients who do not respond within 15-30 minutes.

Aminophylline should be given intravenously to those patients who do not respond to nebulised bronchodilators. It is given as a loading dose of 5 mg/kg/hour as an infusion. The loading dose should be avoided in patients who have been given intravenous aminophylline prior to hospital admission and in those who are already on oral methyl xanthines.

Corticosteroids .

Hydrocortisone sodium succinate 200-500 mg intravenously 4-6 hourly in severely ill patients.

Oral prednisolone in a loading dose of 40-60 mg and thereafter 20 mg 6 hourly in less severely ill patients.

Role of magnesium sulphate administered intravenously or by nebulisation is controversial.

Endotracheal intubation and mechanical ventilation in patients who do not respond to above measures. Indica¬tions for intubation include cardiac or respiratory arrest, severe hypoxia (Pa02 50 mmHg), acidosis (pH < 7.3), exhaustion or deterioration in mental status.

Non-invasive ventilation using continuous positive pressure or bi-level positive airway pressure machines and tight-fitting face mask helps in assisting breathing. It reduces the work of breathing without intubation. It is indicated in a cooperative and alert patient who has impending respiratory failure but does not need immediate intubation.

Treatment with 70-80% helium with oxygen may be beneficial. This mixture reduces airway resistance and improves efficacy of bronchodilators.

Response to treatment is assessed from patient distress, respiratory rate, heart rate, presence of pulsus paradoxus and serial arterial blood-gas studies.