Asthma is a chronic disease commonly defined as reversible narrowing of the airways caused by hypersensitivity of the airways and inflammation. It affects 5-8% of the global population1. When the airways come into contact with an asthma trigger, an immune cascade where mast cells are recruited to the bronchial smooth muscles and release inflammatory mediators such as leukotrienes, histamine and prostaglandins is activated. Thus, these inflammatory mediators cause the bronchocontriction, increased mucous production and mucousal swelling which is commonly associated with asthma2. There has also been evidence showing that type 2 T helper cells (Th2 cells) have a major role in initiating the immune cascade which causes the symptoms of asthma and activation of Th2 lymphocytes appears to be specific for asthma and there is a positive correlation between the degree of activation of Th2 lymphocytes and the severity of asthma 3. Cigarette smoke, cold air ,exercise and allergens like dust or pollen trigger asthma exacerbations in susceptible individuals and a patient is more likely to be susceptible to asthma if there is a string family history of asthma or the patient also has other atopic conditions like eczema or hay fever 1. Currently there doesn't appear to be any fixed method of diagnosis for asthma and it is based on looking out for a certain symptom pattern and ruling out other possible causes for these symptoms. Asthma patients who are suffering from exacerbations commonly present with symptoms such as difficulty breathing, wheezing, coughing and chest tightness. Wheezing is commonly misused as a generic term for any abnormal respiratory sound but it is important to noter that wheezing is actually a specific continuous high pitched sound from the patient's chest. A lowered FEV1(forced expiratory volume in 1 second) or PEFR(peak expiratory flow rate) is also a cardinal sign of an asthma exacerbation. These symptoms are usually worse at night and the patient might suffer from night time awakenings due to trouble breathing 4.Airway obstruction is also an important characteristic of asthma as opposed to airway restriction. Airway obstruction is where a patient's FEV1/FVC (forced vital capacity) ratio is less than 0.7 which indicates that the patient has a normal lung function (normal volume of air exhaled by lungs) but obstructed airways which interfere with exhalation of air from lungs, leading to less air expired in 1 second hence, lowered FEV1. Whereas with airway restriction, the FEV1/FVC ratio is close to normal, indicating that shortness of breath is due to lung problems and not problematic airways. Spirometry is the preferred method for measuring FEV1 and FVC as it is less effort dependent and can record the reversibility of the bronchoconstriction better. 4,5.Airway responsiveness tests are also used to determine the responsiveness of airways to irritants such as histamine, methylcholine or mannitol 6.Airway responsiveness is measured by the concentration of irritant needed to cause a 20% drop in FEV1. Although this test is sensitive for asthma, it is rather non specific as it doesn't rule out other possible causes of airway obstruction 7.Other tests such as skin allergen tests and measurements of sputum eosino phil levels are also helpful in the diagnosis of asthma 5.
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The British Thoracic Society (BTS) 4guidelines recommend a 5 step treatment plan where the patient goes up a stage on the treatment plan if the previous treatment fails to control the asthma well enough. Well controlled asthma is defined as an absence of night time awakenings caused by asthma, no symptoms of asthma in the daytime, no need for emergency medications, no exacerbations and normal lung function (FEV1 or PEF is >80% of predicted or patient's best value) and no limits on the patient's physical quality whatsoever. Basically a good control on asthma aims to bring the patient's quality of life to as close as normal as possible. In the first step of treatment, the patient doesn't receive any long term treatment as prophylaxis but only a short acting inhaled bronchodilator to be used in case of emergency exacerbations. The most commonly used short acting bronchodilator is salbutamol which is a β2 agonist and causes bronchodilation by acting on bronchial β2 receptors 8 Ipratropium bromide, an anti-cholinergic rapid acting bronchodilator is also used in the acute management of severe asthma exacerbations along with salbutamol. It acts by affecting the nervous regulation of the airways.12
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The second step of treatment introduces regularly inhaled corticosteroids into the treatment plan.
This step of treatment is indicated for those who are symptomatic ≥ 3 times a week, need to use a rapid acting bronchodilator ≥ 3 times a week and have one night time awakening caused by asthma.
Commonly used corticosteroids include budesonide and beclomethasone. These corticosteroids act by exerting an anti-inflammatory effect on the bronchial airways. It has been postulated that they influence the expression of certain genes which results in modification of the inflammatory response which causes asthma 9.They also act by inhibiting the release of inflammatory mediators which act on the bronchial smooth muscle and cause bronchoconstriction.10 They have also been shown to reduce the increased blood flow to airways which reduces the inflammation there.11 Inhaled corticosteroids should be given on a twice daily basis (e.g. beclomethasone 400mcg bd).4
The third step of the treatment plan is to add on a long acting β2 agonist such as salmeterol in addition to the inhaled corticosteroid. The fourth step of treatment involves adding on a leukotriene antagonist such as montelukast or zafirlukast. Then the final step of treatment involves adding on an oral corticosteroid which is taken on a regular basis.4 Oral corticosteroids are also used in the acute management of severe exacerbations where they act the same way as inhaled corticosteroids.
This patient is shown to be on the second step of asthma treatment and therefore was using inhaled salbutamol 100mcg when needed and inhaled budesonide 400mcg twice daily. She was also given IV hydrocortisone 100mg three times daily, A:V:N (Atrovent: Ventolin: NaCl 0.9%) 2:1:2 nebuliser 6 hourly and co-amoxiclav for her acute asthma exacerbation.
A study comparing the bronchodilating effects of nebulised salbutamol, sodium cromoglicate and a placebo consisting of sterile water in asthmatics found that salbutamol was significantly more potent than sodium cromoglicate as a bronchodilator. However, it found that the placebo accounted for half the bronchodilating action demonstrated in this study and it was hypothesised that this is due to the effect of water on the surface film of the surfactant in the bronchial airways.13 In another clinical trial, a racemic mixture of salbutamol, R-salbutamol, S-salbutamol and a placebo were all studied for their effects on bronchoconstriction induced by methacholine. R-salbutamol and a salbutamol racemic mixture both showed the same degree of bronchodilation whereas S-salbutamol barely had any bronchodilating effect. Either way, it still showed that the racemic mixture (which is the commercially available product used in asthma treatment) and R-salbutamol had a statistically significant bronchodilating effect compared to the placebo.14 As mentioned earlier, salbutamol is used for rapid relief of asthma symptoms and thus is recommended to be used on an 'as needed' basis.4,5 A clinical trial comparing regular use of inhaled salbutamol (400mcg qds) for two weeks versus as needed use of salbutamol showed no difference in symptomatic relief between the two dosage regimens but some advantage in symptomatic control for regular dosing of inhaled salbutamol.15 These findings only apply in those with moderate asthma however as another similar study showed that there was a regular dosage regimen of inhaled salbutamol had no advantage whatsoever over using salbutamol only when needed in patients with mild asthma.16 However there has been some concern that regular use of a short acting β2 agonist may have negative effects on asthma control and increase asthma related mortality 17,18. A TRUST randomised trial set out to investigate these claims and found that regular use of salbutamol didn't have any negative effect over asthma control 19. A Cochrane review found that in general, regular use of inhaled salbutamol didn't have any significant benefit over inhaled salbutamol used only when needed, however it also found that regular salbutamol use didn't have any detrimental effect on asthma control 20.
As mentioned earlier, inhaled corticosteroids are given as first line treatment for persistent asthma as prophylaxis against asthma exacerbations 4,5. There has been plenty of evidence showing that inhaled corticosterioids are beneficial in asthma control. Two Cochrane reviews comparing budesonide versus a placebo and beclomethasone versus a placebo respectively found that both of them were effective in improving asthma control compared to a placebo 21,22. Inhaled corticosteroids have also been shown to generally improve the patient's perception of their quality of life by not only reducing the number of exacerbations but also improving general feeling of vitality and wellbeing 23. A systematic review has shown that 800mcg-1600mcg of inhaled budesonide daily has a clinically significant benefit in terms of reducing the number of exacerbations over 200mcg of inhaled budesonide a day in those with moderate to severe asthma. However there doesn't seem to be any clear benefits in increasing the inhaled corticosteroid does for those with mild asthma24. Inhaled corticosteroids are also a substitute for long term oral corticosteroid therapy for those with severe chronic asthma. A study comparing the side effects of nebulised budesonide versus oral prednisolone showed that there was significant dose related suppression in morning cortisol levels, serum osteocalcin levels and blood eosinophil levels for oral prednisolone but none for inhaled budesonide, suggesting that systemic side effects are less pronounced for inhaled corticosteroids compared to systematic corticosteroids 25.
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Systemic corticosteroids are also recommended for acute asthma attacks and are to be continued for at least 5 days after the acute attack to prevent relapse 4,5. A Cochrane review analysing randomised controlled trials regarding systemic corticosteroid use in emergency exacerbations found that early administration of systemic corticosteroids (within 1 hour of presenting to emergency department) reduced the need for admission and improved PEF rates 26. Another review showed that lower doses of systemic corticosteroids were just as effective as high doses in treating acute exacerbations 27. The BTS and GINA guidelines recommend 40-50mg of oral prednisolone or equivalent 4,5. It has been shown that oral corticosteroids are successful in preventing relapse in patients with a recent asthma exacerbation 28. There has also been evidence that oral corticosteroids are just as effective as IV corticosteroids in treating acute asthma exacerbations, thus supporting current guideline recommendations 4,5,29,30.
Nebulised ipratropium bromide in combination with salbutamol is recommended to be given in acute severe exacerbations where the patient is has initial poor response to a short acting β2 agonist. The recommended dose is 0.5mg 4 to 6 hourly 4,5. There have been various studies investigating the effect of ipratropium bromide combined with salbutamol on acute asthma exacerbations versus salbutamol alone and it is safe to say that there is sufficient evidence showing that there is a benefit in giving nebulised ipratropium bromide together with salbutamol compared to giving salbutamol alone 31,32,33. However, it has not been shown to be of much benefit in mild cases of asthma as the use of salbutamol might already have caused maximum bronchodilation and thus, ipratropium bromide's additional bronchodilating effects can't be seen 32.
BTS and GINA guidelines do not recommend the routine use of antibiotics in acute asthma exacerbations unless there is proof there is a bacterial infection as in most exacerbations where the trigger is an infection, the cause is more commonly viral and not bacterial 4,5. A clinical trial conducted by Graham and colleagues to investigate the effect of amoxicillin vs. a placebo on asthma recovery found that there was no significant difference between both groups in terms of symptom improvement, respiratory function, patient's general feeling of well being and length of hospital stay 34. A Cochrane review also found that routine prescribing of antibiotics in acute asthma patients had no clear benefit, although the studies included in the review were small so there needs to be more research on this topic 35. However, since there is a lack of evidence advocating the routine use of antibiotics in acute asthma, it shouldn't be used as needless use of antibiotics is not only an unneccesarry cost but also might worsen the problem of bacterial resistance. Also in the case of penicillins, it might prove to be an allergenic risk.
In this case, the patient was given IV hydrocortisone 100mg thrice daily and then changed to oral prednisolone 30mg once daily. The recommended dose for an adult would be either IV hydrocortisone 100mg four times daily or 40-50mg oral prednisolone once daily. Therefore this is a subtherapeutic dose and might not have the desired effect. Also, as shown above, oral corticosteroids are just as effective as intravenous corticosteroids for managing acute asthma attacks. The oral route is also safer and more cost effective as in intravenous administration there is a risk of infection at the injection site and also new equipment such as needles and syringes have to be used with each dose. The patient was also given IV co-amoxiclav 1.2g thrice daily and then switched to oral co-amoxiclav 625mg twice daily. Evidence (as shown above) has indicated that there is no proof that administration of antibiotics is beneficial in acute asthma and in this patient, there are no sign of bacterial infection. In fact judging from her symptoms it is much more likely that it is a viral infection rather than a bacterial infection. Also the dose of 625mg twice daily is not appropriate as co-amoxiclav is given on a thrice daily basis and inappropriate dosing like this might affect the steady state concentration and time needed to reach steady state 36.