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This figure is predicted to rise to 400 million by 2025. Ireland has the fourth-highest prevalence of asthma in the world (9.8 per cent), with an estimated 5,000 asthma-related hospital admissions and 20,000 emergency department attendances annually. Asthma causes over 239,000 deaths in the world annually and is responsible for a significant burden of disability, similar to the disability-adjusted life years (DALYS) seen in diabetes, cirrhosis and schizophrenia.
Despite advances in the understanding and management of asthma, patients with poorly-controlled asthma present a serious problem to physicians. Patients with uncontrolled or severe disease have a higher risk of mortality and a poorer prognosis in terms of declining lung function.
Many people have poor control of their symptoms while on low-to-medium inhaled corticosteroids (ICS). The current guidelines from the Global Initiative for Asthma (GINA) advise physicians to take a stepwise approach to the pharmacological management of asthma. First-line therapy includes low-dose ICS as a ‘controller’ with a short-acting beta agonist (SABA) acting as a ‘reliever’, which can be increased to a medium/high dose ICS with the addition of a long acting beta agonist (LABA), or a leukotriene receptor antagonist (LTRA) in severe cases. However, there has been concern over the safety of LABA use in asthmatic patients. A meta-analysis by Salpeter et al showed that LABAs increase severe and life-threatening asthma exacerbations, as well as asthma-related deaths. These concerns have led to a search for alternative controller agents.
The use of anticholinergic agents (antimuscarinics) in asthma management is relatively new. In 2004, a Cochrane review examined the use of anticholinergic agents, such as ipratropium bromide, in chronic asthma and found that there was no justification for using anticholinergics as an additional therapy in patients whose asthma was poorly controlled on standard treatments. The review concluded that the use of a long-acting anticholinergic (LAMA) such as tiotropium in patients with asthma had not been established and suggested further trials into its use in this cohort of patients. Tiotropium has a duration of action of 24 hours and was approved by the Food and Drug administration (FDA) in 2004 for the treatment of chronic obstructive pulmonary disease (COPD), but not for asthma. Several studies have since shown that the addition of tiotropium to standard asthma treatment regimens increases their efficacy.
In this article, we review current evidence and guidelines for the management of asthma. We also consider novel approaches, such as the use of long-acting anticholinergics in uncontrolled asthma and immunotherapy for concomitant allergic rhinitis.
A case history of difficult-to-control asthma is presented above, with a specific focus on the role of such therapies in practical management.
GINA was founded in 1993 in collaboration with the World Health Organisation and the National Heart Lung and Blood Institute in the US. The main aim of GINA is to reduce the prevalence, morbidity and mortality associated with asthma globally by making recommendations for the management of asthma, based on the best evidence-based medical and scientific information available. The current GINA guidelines (2014) for asthma management involve a three-pronged approach, including pharmacological treatment, risk factor modification and non-pharmacological strategies, with the long-term goals of symptom control and risk reduction.
The pharmacological treatment of asthma is based on the severity of symptoms and an awareness of the risk factors for poor asthma outcomes. The severity of asthma is based on the patient’s symptoms over the previous month, including: daytime symptoms more than twice a week; night waking due to symptoms; the use of relievers more than twice a week; and limitation of activities due to symptoms. Patients who meet three or four of these criteria are said to have ‘uncontrolled’ asthma.
Risk factors for poor outcomes in asthma for exacerbations include: uncontrolled symptoms; no ICS; excessive use of relievers; poor inhaler technique; pregnancy; smoking; blood eosinophilia; and a poor FEV1, particularly if less than 60 per cent predicted. Risk factors for poor asthma outcomes for fixed airflow limitation include lack of ICS treatment, low FEV1, smoking, chronic mucous hypersecretion and occupational exposures. The risk factors for medication side-effects include long-term, high-dose ICS, frequent use of P450 inhibitors and frequent oral steroid use.
Pharmacological management of asthma takes a stepwise approach based on symptoms, exacerbations, side-effects, patient satisfaction and lung function. Step 1 involves commencing a low-dose ICS as a controller, with a SABA as a reliever. Step 2 advises the use of a low-dose ICS or LTRA or low-dose theophylline with a SABA reliever. Step 3 involves low-dose ICS with a LABA, progressing to medium-to-high dose ICS with a LABA or high-dose ICS with LKTA in step 4. In more severe cases, step 5 recommends referring the patient for anti IgE treatment and commencing oral corticosteroids. SABA or ICS/formoterol can be used as a reliever in steps 3 to 5. Treatment can be stepped up or down by assessing the patient’s symptoms, adjusting the treatment and reviewing the response. In an acute exacerbation of asthma, GINA guidelines advise the use of nebulised SABA, oral steroids, ipratropium bromide and magnesium sulphate in severe exacerbations.
The guidelines also highlight several other important issues to consider for all patients with asthma, including the need for a written asthma action plan, training in inhaler skills, self-monitoring, including a peak flow diary, as well as regular medical review.
Tiotropium is a long-acting anticholinergic bronchodilator widely used in the treatment of COPD. However, several recent studies have shown its efficacy in improving outcomes in patients with uncontrolled asthma when used as an additional therapy to the standard treatment regimen in severe asthma of ICS and LABA.
In 1996, O’Connor et al published a study in the American Journal of Respiratory and Critical Care Medicine showing that tiotropium had a prolonged bronchodilator response. They concluded that it may be useful in the treatment of nocturnal asthma and that once-daily dosing could be enough.
Kerstjens et al conducted two replicate, randomised, controlled trials between 2008 and 2011, including 912 patients with poorly-controlled asthma who were on standard ICS and LABA combination therapy. The study compared the effects on lung function and exacerbation of adding tiotropium as a once-daily dose of 5 micrograms or placebo over a 48-week period. The addition of tiotropium increased the time to the first severe exacerbation by 56 days, with an overall reduction of 21 per cent of the risk of a severe exacerbation. A study published in 2010 by Peters et al found that the addition of tiotropium to an ICS improved symptoms and lung function in patients with inadequately-controlled asthma. Moreover, its effects appeared similar to those with the addition of salmeterol to ICS therapy.
Phase III trials have shown that the addition of tiotropium to ICS therapy in patients with poorly-controlled asthma resulted in improved lung function. Moreover, these trials also showed that the addition of tiotropium to an ICS consistently reduced exacerbations across patients with asthma of different severities.
Overall, phase III trials showed that the addition of tiotropium to patients on a standard therapy of ICS and LABA reduced the number of patients who had a severe asthma exacerbation by 26.9 per cent vs 32.8 per cent, delayed the time to first episode of asthma worsening (315 days vs 181 days) and reduced the risk of a severe asthma exacerbation by 21 per cent.
In October 2014, tiotropium was licensed as Spiriva Respimat for use in adults with asthma as an add-on maintenance bronchodilator treatment in adult patients with asthma who were on maintenance combination of ICS and LABA and who had experienced one or more severe exacerbations in the previous year.
Recent reports of modifying the allergic response in patients with peanut allergy by repeated allergen exposure have generated considerable interest in the lay press. Manipulation of the immunologic response contributing to allergic rhinitis has been licenced in Europe for some time.
Sublingual immunotherapy (SLIT) involves administering a fixed-dose of an allergen intraorally in an attempt to reduce the subsequent reaction when that antigen is encountered again. Oralair and Grazax are available in Ireland for the management of grass pollen-induced rhinitis, with or without conjunctivitis. Both contain grass pollen extract, which is administered in tablet form under the tongue. Suitable patients can be identified by skin-prick testing.
Serum-specific IgE can also be measured but this is more costly, with delayed results. There is no evidence to suggest that IgG measurement has any role in patient selection. The treatment is administered over three years or more.
Several studies, including a meta-analyses by Penagos et al, confirm that SLIT significantly reduces clinical symptoms and the use of anti-allergic drugs in allergic rhinitis. The efficacy in allergic asthma is still debated, with some meta-analyses showing clear effectiveness but others giving contrasting results. SLIT is a safe and effective treatment for allergic rhinitis, reducing symptoms by up to 50 per cent.
Despite its safety, it is recommended that the first dose is given under medical supervision. The effects persist for at least three years after stopping treatment and there is some evidence that SLIT may prevent the development of asthma in patients with allergic rhinitis. Antigens other than grass are available but have to be given in more expensive and less convenient droplet form. Anticipated development of other antigen tablets, particularly relating to house dust mites, should broaden the appeal of this novel and effective therapy.
A rising prevalence of asthma globally has resulted in increased morbidity and mortality for patients, as well as an increased burden on health systems and economies.
The management of patients with uncontrolled or difficult-to-control asthma still presents a significant challenge to the medical community.
GINA provides a comprehensive set of guidelines for the management of these patients, focused on patient education, written asthma action plans, regular medical review and pharmacological therapies. Recent studies have shown that novel therapies such as sublingual immunotherapy and tiotropium can be effective in difficult-to-control cases.
References on request
A 17-year-old female was referred to the respiratory service by her GP with a four-year history of poorly-controlled asthma, which had been gradually deteriorating, requiring several courses of oral steroids and antibiotics.
She initially presented to her GP with wheeze and dry cough, which was treated acutely with oral steroids.
The patient was atopic as a child, suffering from seasonal allergic rhinitis as well as reactions to cats and dogs. However, she only began wheezing in her mid-teens. There was no family history of asthma, no smokers at home and her house was fully renovated, with no damp or mould.
She was commenced on maintenance budesonide and salbutamol metered dose inhalers. Despite this, she returned to her GP with continued wheeze and cough. Her medication was changed to a low-dose budesonide/formoterol combination dry power inhaler. She was given fluticasone nasal spray for a concurrent history of atopic rhinitis. Her symptoms initially improved but she subsequently had several exacerbations, with prolonged episodes of wheeze and cough which required courses of oral steroids. Her GP commenced her on montelukast, which improved her symptoms but the episodes of wheeze and cough persisted.
At first assessment at the respiratory clinic, the patient’s chest was clear on auscultation and percussion. Her oxygen saturations were 96 per cent on room air and her peak flow was 400L/minute. There was evidence of a post-nasal drip and her inhaler technique was poor. Her history was noted and her medications were changed as follows: budesonide/formoterol dose was increased and a nasal sinus rinse was introduced. She commenced a peak flow diary.
The patient reported an initial moderate improvement in symptoms with this therapy but at a follow-up consultation six weeks later, her peak flow was down to 350L/min and symptoms had increased in severity, with wheeze and rhinorrhoea. Compliance was reviewed with the patient and her family. Budesonide/formoterol was changed to high-dose fluticasone/salmeterol dry power inhaler, on which she subsequently developed intolerable oral candidiasis. A reduction of fluticasone/salmeterol dose improved her oral side-effects but caused her asthma symptoms to return. She commenced nebulised fluticasone, as well as continuing inhaled salmeterol. Her nasal symptoms persisted despite good use of prescribed nasal therapies and the patient was referred to ENT to assess the need for surgical management of her nasal symptoms. Examination revealed a very active allergic rhinitis, which considerably improved with a six-week course of dexamethasone drops and intranasal antihistamines.
However, six months later she was admitted to the hospital with an acute exacerbation of asthma requiring oxygen, nebulised bronchodilators and intravenous steroids. She received education on control of breathing and managing unexpected symptoms from a respiratory physiotherapist during her stay. At her follow-up assessment, she was evaluated for sublingual immunotherapy (SLIT). Skin-prick testing confirmed her atopic status. Grass and house dust mites were identified as major allergens. She was scheduled to commence sublingual grass pollen extract the following February and was advised on control measures for house dust mites and on the use of intermittent antihistamines. She was commenced on inhaled tiotropium and continued her other asthma and rhinitis treatments.
Twenty-four months following presentation, she is maintained on standard doses of inhaled and topical nasal steroids. She has discontinued nebulised therapy. She takes montelukast regularly and antihistamines as required. She uses short-acting bronchodilators less than once per week and she has not had a further hospital admission. Her asthma and rhinitis are under excellent control and she is physically active and successfully pursuing a third-level qualification.