Asthma Management Handbook

Managing severe, high-risk and difficult-to-control asthma in adults

Recommendations

Consider referral to a specialist respiratory physician with an interest in asthma for people with severe, high-risk or difficult-to-control asthma, including those with any of the following:

  • persistent asthma symptoms despite adequate treatment taken correctly. (For most people, good asthma symptom control can be achieved by following the stepped approach to adjusting medication.)
  • a requirement for high-dose inhaled corticosteroids to maintain asthma control (after checking and correcting inhaler technique and confirming adherence)
  • flare-ups or chest infections more than once a year
  • a history of life-threatening asthma (including any previous admission to intensive care for asthma)
  • a previous presentation to an emergency department for acute asthma
  • systemic or severe treatment-related adverse effects
  • persistent sputum production
  • persistent poor adherence to preventer treatment or psychosocial factors that prevent effective treatment
  • clinical features that could suggest an alternative diagnosis (e.g. atypical symptoms, normal spirometry during symptoms)
  • significantly discordant symptoms and spirometry (e.g. frequent symptoms but normal lung function, or few interval symptoms but frequent or sudden flare-ups or FEV1 <70% predicted when well)
  • troublesome comorbidities such as marked obesity or frequent rhinosinusitis
  • other risk factors for adverse outcomes.

Table. Definition of levels of recent asthma symptom control in adults and adolescents (regardless of current treatment regimen)

Good control

Partial control

Poor control

All of:

  • Daytime symptoms ≤2 days per week
  • Need for reliever ≤2 days per week
  • No limitation of activities
  • No symptoms during night or on waking

One or two of:

  • Daytime symptoms >2 days per week
  • Need for reliever >2 days per week
  • Any limitation of activities
  • Any symptoms during night or on waking

Three or more of:

  • Daytime symptoms >2 days per week
  • Need for reliever >2 days per week
  • Any limitation of activities
  • Any symptoms during night or on waking

† Not including SABA taken prophylactically before exercise. (Record this separately and take into account when assessing management.)

Note: Recent asthma symptom control is based on symptoms over the previous 4 weeks.

Adapted from:

Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention. GINA, 2012. Available from: http://www.ginasthma.org/

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Table. Risk factors for adverse asthma outcomes in adults and adolescents Opens in a new window Please view and print this figure separately: https://www.asthmahandbook.org.au/table/show/40

Table. Management of risk factors for adverse asthma outcomes in adults

Risk factor

Clinical action †

Any risk factor for flare-ups

Check patient has an appropriate action plan

Carefully check inhaler technique and adherence, and identify any barriers to good adherence

Review frequently (e.g. every 3 months)

Hospitalisation or ED visit for asthma or any asthma flare-up during the previous 12 months

Ask about triggers for flare-ups, and lead time

History of intubation or intensive care unit admission for asthma

Ensure action plan recommends early medical review when asthma worsens

Hospitalisation or ED visit for asthma in the past month

Emphasise importance of maintaining regular ICS use after symptoms improve

Confirm that patient has resumed using SABA only when needed for symptoms

High SABA use (>2 canisters per month)

Check lung function

If SABA use appears to be habitual, investigate causes and consider alternative strategies, e.g. short-term substitution of ipratropium for SABA

Long-term high-dose ICS

Consider gradual reduction of ICS dose if symptoms stable

Monitor regularly (e.g. assessment of bone density, regular eye examinations)

For local side-effects, ensure inhaler technique is appropriate

Poor lung function (even if few symptoms)

Consider 3-month trial of higher ICS dose, then recheck lung function

Consider referral for detailed specialist investigation

Sensitivity to unavoidable allergens (e.g. Alternaria species of common moulds)

Refer for further investigation and management

Exposure to cigarette smoke (smoking or environmental exposure)

Emphasise the importance of avoiding smoke

Provide quitting strategies

Consider increasing ICS dose (higher dose of ICS likely to be necessary to control asthma)

Refer for assessment of asthma–COPD overlap

Difficulty perceiving airflow limitation or the severity of exacerbations

Regular PEF monitoring

Action plan should recommend early review and measurement of lung function

No current written asthma action plan

Provide and explain written asthma action plan

† In addition to actions applicable to all risk factors

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Figure. Stepped approach to adjusting asthma medication in adults Opens in a new window Please view and print this figure separately: https://www.asthmahandbook.org.au/figure/show/31

How this recommendation was developed

Consensus

Based on clinical experience and expert opinion (informed by evidence, where available), with particular reference to the following source(s):

  • Chung et al. 20141

Montelukast can be considered as an add-on option in patients with difficult-to-treat asthma who are already taking other preventers.

Note: PBS status as at October 2016: Montelukast treatment is not subsidised by the PBS for people aged 15 years or over. Special Authority is available for DVA gold card holders, or white card holders with approval for asthma treatments.

How this recommendation was developed

Consensus

Based on clinical experience and expert opinion (informed by evidence, where available), with particular reference to the following source(s):

  • Ducharme, 20042

Tiotropium via mist inhaler can be considered as an add-on option in adults who have had a severe asthma flare-up within the previous year despite maintenance treatment with inhaled corticosteroid (equivalent to 800 mcg budesonide/day or higher) in combination with a long-acting betaagonist.

How this recommendation was developed

Consensus

Based on clinical experience and expert opinion (informed by evidence, where available), with particular reference to the following source(s):

  • Anderson et al. 20153
  • Kew et al. 20164
  • Rodrigo et al. 20155

Consider a trial of treatment with a small-particle inhaled corticosteroid (e.g. beclometasone [Qvar], ciclesonide) for patients with difficult-to-treat asthma, those with persistently low lung function despite regular treatment with inhaled corticosteroids, or those who experience significant oral/laryngeal adverse effects while taking other inhaled corticosteroids.

How this recommendation was developed

Consensus

Based on clinical experience and expert opinion (informed by evidence, where available), with particular reference to the following source(s):

  • Leach et al. 20096

Omalizumab treatment can be considered for adults and adolescents aged 12 years and over, with moderate-to-severe allergic asthma despite inhaled corticosteroid treatment, and raised IgE levels.

​Note: For adults and adolescents with severe allergic asthma who may be eligible for PBS subsidy, whose asthma is not well-controlled despite optimal inhaled therapy, refer immediately for specialist assessment, because patients only become eligible for PBS subsidisation for omalizumab after at least 12 months’ care by a specialist experienced in the management of severe asthma. After treatment is established, ongoing treatment with omalizumab may be administered by a GP, with 6-monthly review of ongoing eligibility at the specialist clinic.

How this recommendation was developed

Adapted from existing guidance

Based on reliable clinical practice guideline(s) or position statement(s):

  • Katelaris et al. 20097
  • Chung et al. 20141

Mepolizumab can be considered as an add-on treatment for patients aged 12 years and over with severe refractory eosinophilic asthma. Mepolizumab is given by subcutaneous injection every 4 weeks.

Note: For adults and adolescents with severe allergic asthma who may be eligible for PBS subsidy, whose asthma is not well-controlled despite optimal inhaled therapy, refer for specialist assessment, because patients only become eligible for PBS subsidisation for mepolizumab after 12 months of treatment by a specialist experienced in the management of severe asthma.

How this recommendation was developed

Consensus

Based on clinical experience and expert opinion (informed by evidence, where available), with particular reference to the following source(s):

  • Menzella et al. 20168
  • Powell et al. 20159

More information

Definitions of severe and difficult-to-treat asthma

Although most people's asthma can be effectively treated with currently available medicines, a substantial subset of people have uncontrolled asthma (as indicated by persisting symptoms, low lung function and/or flare-ups) despite treatment. These patients are described as having difficult-to-treat asthma.

Some patients with difficult-to-treat asthma have severe asthma. Asthma severity is classified retrospectively according to the level of treatment needed to achieve or maintain good asthma control, rather than by the intensity or frequency of symptoms.10 International guidelines have been published for the assessment and management of patients with severe asthma.1 'Severe asthma' (also called severe refractory asthma' or 'severe treatment-resistant asthma') is defined as asthma for which good control is not achieved despite the highest level of recommended treatment, or asthma for which control can be maintained only with the highest level of recommended treatment.1 It is estimated that 5-10% of patients with asthma have severe asthma.1

Not all patients with difficult-to-treat asthma have severe asthma. 'Difficult-to-treat asthma' includes asthma that is uncontrolled due to adherence issues, inappropriate or incorrect use of medicines, environmental triggers or comorbidities. Patients whose asthma control improves rapidly with correction of such problems are not considered to have severe asthma.1

Treatment-resistant asthma or severe refractory asthma can only be diagnosed after confirming the diagnosis, confirming good adherence to high-dose inhaled corticosteroid and correct inhaler technique, excluding alternative or overlapping diagnoses, identifying and minimising exposure to preventable triggers including allergens, irritants and medicines that cause bronchoconstriction, managing comorbidities, and closely monitoring for at least 6 months.111

Omalizumab is a treatment option for some adults, adolescents and children with severe asthma.

The definition of severe asthma proposed by the World Health Organization (WHO) Consultation on Severe Asthma for global use is 'uncontrolled asthma which can result in risk of frequent severe exacerbations (or death) and/or adverse reactions to medications and/or chronic morbidity (including impaired lung function or reduced lung growth in children)'.12 The WHO definition of severe asthma includes a category called 'severe untreated asthma', a term recommended only for use in countries that lack access to standard asthma medications such as inhaled corticosteroids.

Patients with severe symptoms due to untreated asthma may be found, after starting regular treatment, to have mild asthma (i.e. asthma that is easily controlled with low-dose inhaled corticosteroids).10

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Inhaled corticosteroids for adults: adverse effects

Local adverse effects

Hoarseness (dysphonia) and candidiasis are the most common local adverse effects of inhaled corticosteroids with both pressurised metered-dose inhalers and dry-powder inhalers:13

  • The rate of of dysphonia among patients taking inhaled corticosteroids has been estimated at 5–20%.14 However, higher rates of up to 58% have been reported in some studies.15 The risk varies with the device used.
  • The rate of oropharyngeal candidiasis among adults using inhaled corticosteroids has been estimated at 5–7%, with positive mouth culture for Candida albicans in approximately 25% of patients. However, higher rates of up to 70% have been reported in some studies. The risk depends on the formulation, dose and dose frequency.14

When taking inhaled corticosteroids via pressurised metered-dose inhalers, the use of a spacer reduces the risk of dysphonia and candidiasis.16 Spacers improve delivery of the medicine to the airways.

Rinsing the mouth with water after inhaling reduces the risk of oropharyngeal candidiasis.16 Quick mouth rinsing immediately after inhaling effectively removes a high proportion of remaining medicine.17

The incidence of dysphonia and candidiasis is significantly lower with ciclesonide than with equivalent doses of fluticasone propionate.18 This may an important consideration for patients who experience dysphonia, particularly for those for whom voice quality is important (e.g. singers, actors, teachers). With ciclesonide, the rate of adverse effects may not differ when taken with or without a spacer.19

Systemic adverse effects

Cross-sectional population studies have reported lower bone mineral density with long-term use of high doses of inhaled corticosteroid,20 but the effect on fracture risk in patients with asthma is unclear.

A meta-analysis of randomised controlled trials in adults older than 40 years with COPD (in which osteoporosis is more common) or asthma found no association between the use of inhaled corticosteroid and fracture risk overall, but found a slight increase in fracture risk among those using high doses.21

Cross-sectional studies show a dose–response relationship between inhaled corticosteroid use for asthma or COPD, and risk of cataracts in adults.22

Long-term inhaled corticosteroid use for asthma or COPD is associated with a small increase in the risk of developing diabetes, and in the risk of diabetes progression. These risks are greatest at higher doses (equivalent to fluticasone propionate 1000 mcg/day or higher).23

The incidence of osteoporosis, cataracts and diabetes increases with age, and these conditions are also more common in smokers and in patients with COPD. Few studies have assessed risk specifically in patients with asthma.

Patients at risk of osteoporosis should be referred for bone density screening, screened for vitamin D and/or calcium deficiency, and provided with advice about maintaining bone health.

Patient concerns about adverse effects

The prevalence of side effects that patients consider troubling increases with increasing dose of inhaled corticosteroids.24 Mid and high doses are consistently associated with a higher intensity and a higher prevalence of reported adverse effects, after controlling for other factors.24

A high proportion of people with asthma may have misunderstandings and fears about using inhaled corticosteroids,2526 such as fears about weight gain, unwanted muscle development, bone fractures, susceptibility to infections and reduction of efficacy of the medicine over time.25 Most people do not discuss their concerns about inhaled corticosteroid treatment with health professionals.25 Safety concerns are a major reason for poor adherence, particularly general concerns about corticosteroids rather than concerns about specific adverse effects.27

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Inhaled corticosteroids for adults and adolescents: particle size

Medicines with small particle size (CFC-free beclometasone [Qvar] and ciclesonide) achieve a greater proportion of medicine deposited in the lungs,6 and are potentially distributed more widely in the large, intermediate, and small airways.6 However, the clinical implications have not been established.

Randomised controlled trials comparing ciclesonide with fluticasone propionate in adults and adolescents have observed lower rates of patient-reported side-effects,28 and confirmed dysphonia and oral candidiasis,18 among patients using ciclesonide than among those using fluticasone propionate.

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Montelukast for adults: efficacy

In adults and adolescents with asthma that is not controlled by low-dose inhaled corticosteroid, the addition of a leukotriene receptor antagonist is less effective than the addition of a long-acting beta2 agonist in reducing the rate of asthma flare-ups that require treatment with oral corticosteroids.2 The addition of a leukotriene receptor antagonist is also associated with lesser improvement in lung function and quality of life than the addition of a long-acting beta2 agonist.2

Montelukast taken 1 hour before exercise can be used to manage exercise-induced bronchoconstriction, but it is less effective than short-acting beta2 agonists.29

Retrospective analysis of clinical trial data suggests that some people with asthma who smoke,30 or are obese,31 may achieve better asthma control with montelukast than an inhaled corticosteroid. However, prospective studies would be needed to confirm this.

Some individuals may also achieve better asthma control with montelukast than with an inhaled corticosteroid for reasons that are unknown and cannot be predicted from currently available data.

Although montelukast was previously thought to have particular benefits for people with aspirin-intolerant asthma, this has not been consistently demonstrated in clinical trials.

Within specialised severe asthma clinics, montelukast is sometimes prescribed as add-on treatment for adults.​

Note: PBS status as at October 2016: Montelukast treatment is not subsidised by the PBS for people aged 15 years or over. Special Authority is available for DVA gold card holders or white card holders with approval for asthma treatments.

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Montelukast for adults and adolescents: psychiatric effects

Post-marketing surveillance reports led to concerns about a possible association between leukotriene receptor antagonist use and suicide risk.32 A recent case-control study reported a statistically significant association between the use of leukotriene receptor antagonists and suicide attempts in people aged 19–24 years. However, this association was no longer statistically significant after adjusting for potential confounding factors, including previous exposure to other asthma medicines and previous exposure to other medicines associated with suicide.32

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Omalizumab

Omalizumab is a treatment option for some adults and children aged 6 years and over with severe allergic asthma.1 Omalizumab is given by subcutaneous injection every 2-4 weeks, with the dose based on the patient's weight and baseline total serum IgE level.

Omalizumab is approved by the Therapeutic Goods Administration for use in:33

  • adults and adolescents aged 12 years and over with moderate-to-severe allergic asthma that is not controlled while taking inhaled corticosteroid and who have raised IgE levels.
  • children aged 6 to 11 years with severe allergic asthma who have documented exacerbations despite daily high-dose inhaled corticosteroids and who have raised IgE levels.

For PBS-subsidised treatment with omalizumab, patients must meet several additional criteria (see Note).

When given in addition to inhaled corticosteroids in double-blind randomised placebo-controlled trials, omalizumab reduced rates of asthma flare-ups and hospitalisation in patients with moderate or severe allergic asthma.34 In non-blinded studies in patients with severe allergic asthma, omalizumab improved lung function and asthma control, reduced symptoms, severe flare-ups, work or school days lost due to severe flare-ups, and hospitalisations, and improved quality of life.35

Omalizumab treatment is generally well tolerated. The most common adverse events are injection site reactions and, in children aged 6-11 years, pyrexia, upper gastrointestinal pain and headache.33 Anaphylactoid reactions have been reported, including among Australian patients.36 Early reports suggested that omalizumab may be associated with an increased risk of malignancy. However, subsequent pooled results indicate that a causal relationship between omalizumab therapy and malignancy is unlikely.37, 33

Note: Omalizumab treatment in adults and adolescents is subsidised through the PBS for use in patients with severe allergic asthma who meet certain criteria, including monitoring for at least 12 months by a specialist (respiratory physician, clinical immunologist, allergist or general physician) experienced in the management of patients with severe asthma. PBS criteria for continuation of treatment include demonstration of a therapeutic response by recording asthma symptom control, at baseline and after 6 months of treatment, using the 5-item Asthma Control Questionnaire (ACQ-5).

Omalizumab treatment for children aged 6 to 11 years is subsidised through the PBS for use in patients with severe allergic asthma who meet certain criteria, including monitoring for at least 6 months by a specialist (paediatric respiratory physician, clinical immunologist, or paediatrician or general physician experienced in the management of patients with severe asthma, in consultation with a respiratory physician). PBS criteria for continuation of treatment include demonstration of a therapeutic response by recording asthma symptom control, at baseline and after 6 months of treatment, using either the ACQ-5 or Asthma Control Questionnaire interviewer administered version (ACQ-IA), or reduction in time-adjusted exacerbation rates compared with the 12 months before treatment.

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Mepolizumab

Mepolizumab is a biological humanised anti-interleukin-5 (IL-5) monoclonal antibody (human IgG1) which reduces the number of eosinophils in sputum and blood. It is indicated for add-on treatment of severe refractory eosinophilic asthma in patients aged 12 years or over and is administered by subcutaneous injection once every 4 weeks.38

In people with severe eosinophilic asthma, mepolizumab treatment has been shown to reduce the rate of asthma flare-ups, improve health-related quality of life, and reduce the need for systemic corticosteroids.9, 8, 39

Adverse effects include hypersensitivity reactions such as urticaria, angioedema, rash, bronchospasm, hypotension. These generally occur within hours of administration, but reactions up to days after administration have been recorded.38 No cases of anaphylaxis were recorded in a 52-week open-label study of subcutaneous mepolizumab, conducted among patients who had participated in two randomised controlled trials.40

Note: Mepolizumab treatment in adults and adolescents is subsidised through the PBS for use in patients with severe allergic asthma who meet certain criteria, including treatment by a specialist (respiratory physician, clinical immunologist, allergist or general physician) experienced in the management of patients with severe asthma. PBS criteria for continuation of treatment include demonstration of a therapeutic response by recording asthma symptom control, at base line and after 6 months of treatment, using the 5-item Asthma Control Questionnaire (ACQ-5).

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Tiotropium for adults

A meta-analysis of 13 randomised placebo-controlled clinical trials in patients with asthma found that tiotropium as an add-on in patients taking inhaled corticosteroids improved lung function, reduced the rate of flare-ups, and improved asthma symptom control.5 In patients with poorly controlled asthma despite treatment with medium-to-high doses of inhaled corticosteroids, tiotropium was not inferior to salmeterol.5

In patients taking a combination of an inhaled corticosteroid and salmeterol, the addition of tiotropium increased lung function, reduced the rate of flare-ups, and improved asthma symptom control.5

Tiotropium was well tolerated.5

A Cochrane review that included five double-blind, double-dummy trials found that the addition of tiotropium to inhaled corticosteroid therapy reduced the risk of flare-ups requiring systemic corticosteroids and improved lung function, compared with the same dose of inhaled corticosteroid, in adults not taking a long-acting betaagonist.3

Another Cochrane review concluded that tiotropium in addition to the combination of an inhaled corticosteroid and a long-acting beta2 agonist may have additional benefits over inhaled corticosteroid/long-acting betaagonist alone in reducing the need for rescue oral corticosteroids in adults with severe asthma.4

Note: Tiotropium via mist inhaler is approved by TGA as add-on maintenance bronchodilator treatment in adults currently treated with inhaled corticosteroids ≥800 mcg budesonide/day or equivalent plus a long-acting betaagonist who have had one or more severe asthma exacerbations in the previous year.41 Tiotropium via dry-powder inhaler is approved for the treatment of COPD.42

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Bronchial thermoplasty in adults

The bronchial thermoplasty procedure uses thermal energy to ablate smooth muscle within the bronchus. It is currently being investigated as a treatment for patients with asthma that is not well controlled with medical management.

There is limited evidence from which to assess its efficacy. Preliminary findings suggest that it is well tolerated and may reduce the rate of severe flare-ups and emergency department visits.434445464748

This procedure is not widely available in Australia, and its application to patients with asthma using primary care services has not been defined.

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References

  1. Chung, K. F., Wenzel, S. E., Brozek, J. L., et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. The European respiratory journal. 2014; 43: 343-73. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24337046
  2. Ducharme FM. Addition of anti-leukotriene agents to inhaled corticosteroids for chronic asthma. Cochrane Database Syst Rev. 2004; Issue 1: CD003133. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD003133.pub2/full
  3. Anderson, D. E., Kew, K. M., Boyter, A. C.. Long-acting muscarinic antagonists (LAMA) added to inhaled corticosteroids (ICS) versus the same dose of ICS alone for adults with asthma. The Cochrane database of systematic reviews. 2015; : Cd011397. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD011397.pub2/full
  4. Kew, K. M., Dahri, K.. Long-acting muscarinic antagonists (LAMA) added to combination long-acting beta2-agonists and inhaled corticosteroids (LABA/ICS) versus LABA/ICS for adults with asthma. The Cochrane database of systematic reviews. 2016; : Cd011721. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD011721.pub2/abstract
  5. Rodrigo, G. J., Castro-Rodriguez, J. A.. Tiotropium for the treatment of adolescents with moderate to severe symptomatic asthma: a systematic review with meta-analysis. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology. 2015; 115: 211-6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26231467
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  9. Powell, Colin, Milan, Stephen J., Dwan, Kerry, et al. Mepolizumab versus placebo for asthma. **. 2015; : . Available from: http://dx.doi.org/10.1002/14651858.CD010834.pub2
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  16. National Asthma Council Australia. Inhaler technique in adults with asthma or COPD. An information paper for health professionals. National Asthma Council Australia, Melbourne, 2008. Available from: http://www.nationalasthma.org.au/publication/inhaler-technique-in-adults-with-asthma-or-copd
  17. Yokoyama H, Yamamura Y, Ozeki T, et al. Effects of mouth washing procedures on removal of budesonide inhaled by using Turbuhaler. Yakugaku Zasshi. 2007; 127: 1245-1249. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17666876
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  19. Engelstatter R, Szlavik M, Gerber C, Beck E. Once-daily ciclesonide via metered-dose inhaler: Similar efficacy and safety with or without a spacer. Respir Med. 2009; 103: 1643-50. Available from: http://www.resmedjournal.com/article/S0954-6111(09)00195-4/fulltext
  20. Wisniewski AF, Lewis SA, Green DJ, et al. Cross sectional investigation of the effects of inhaled corticosteroids on bone density and bone metabolism in patients with asthma. Thorax. 1997; 52: 853-60. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1758420/
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  22. Weatherall M, Clay J, James K, et al. Dose-response relationship of inhaled corticosteroids and cataracts: a systematic review and meta-analysis. Respirology. 2009; 14: 983-90. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19740259
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  28. van der Molen T, Foster JM, Caeser M, et al. Difference between patient-reported side effects of ciclesonide versus fluticasone propionate. Respir Med. 2010; 104: 1825-33. Available from: http://www.sciencedirect.com/science/article/pii/S095461111000257X
  29. Weiler JM, Anderson SD, Randolph C, et al. Pathogenesis, prevalence, diagnosis, and management of exercise-induced bronchoconstriction: a practice parameter. Ann Allergy Asthma Immunol. 2010; 105: S1-47. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21167465
  30. Lazarus SC, Chinchilli VM, Rollings NJ, et al. Smoking affects response to inhaled corticosteroids or leukotriene receptor antagonists in asthma. Am J Respir Crit Care Med. 2007; 175: 783-790. Available from: http://www.atsjournals.org/doi/full/10.1164/rccm.200511-1746OC
  31. Peters-Golden M, Swern A, Bird SS, et al. Influence of body mass index on the response to asthma controller agents. Eur Respir J. 2006; 27: 495-503. Available from: http://erj.ersjournals.com/content/27/3/495.long
  32. Schumock GT, Stayner LT, Valuck RJ, et al. Risk of suicide attempt in asthmatic children and young adults prescribed leukotriene-modifying agents: a nested case-control study. J Allergy Clin Immunol. 2012; 130: 368-75. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22698520
  33. Novartis Pharmaceuticals Australia Pty Ltd. Product Information: Xolair (omalizumab). Therapeutic Goods Administration, Canberra, 2016. Available from: https://www.ebs.tga.gov.au/
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