Asthma Management Handbook

Planning routine asthma review for children

Recommendations

As a general guide, review the child’s asthma:

  • every 3–6 months when asthma is stable and well controlled
  • 4 weeks after increasing the dose or number of medicines to regain control of partially or poorly controlled asthma
  • 2–4 weeks after a visit to the emergency department or a hospital stay due to acute asthma.

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

Good control Partial control Poor control

All of:

  • Daytime symptoms ≤2 days per week (lasting only a few minutes and rapidly relieved by rapid-acting bronchodilator)
  • No limitation of activities
  • No symptoms§ during night or when wakes up
  • Need for reliever# ≤2 days per week

Any of:

  • Daytime symptoms >2 days per week (lasting only a few minutes and rapidly relieved by rapid-acting bronchodilator)
  • Any limitation of activities*
  • Any symptoms during night or when wakes up††
  • Need for reliever# >2 days per week

Either of:

  • Daytime symptoms >2 days per week (lasting from minutes to hours or recurring, and partially or fully relieved by rapid-acting bronchodilator)
  • ≥3 features of partial control within the same week

† e.g. wheezing or breathing problems

‡ child is fully active; runs and plays without symptoms

§ including no coughing during sleep

# not including short-acting beta2 agonist taken prophylactically before exercise. (Record this separately and take into account when assessing management.)

* e.g. wheeze or breathlessness during exercise, vigorous play or laughing

†† e.g. waking with symptoms of wheezing or breathing problems

Note: Recent asthma control is based on symptoms over the previous 4 weeks. Each child’s risk factors for future asthma outcomes should also be assessed and taken into account in management.

Adapted from

Global Initiative for Asthma (GINA). Global strategy for the diagnosis and management of asthma in children 5 years and younger. GINA, 2009. Available from: http://www.ginasthma.org/

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How this recommendation was developed

Consensus

Based on clinical experience and expert opinion (informed by evidence, where available).

At each asthma review, assess recent asthma symptom control and future risk:

  • recent asthma symptom control based on reported symptoms, limitation of daily activity and need for reliever medicine
  • lung function using spirometry (for children old enough to perform the test)
  • adherence to treatment
  • inhaler technique
  • whether the written asthma action plan is up to date
  • modifiable environmental factors
  • whether the child has any risk factors for poor asthma outcomes in future (e.g. persistent symptoms, difficult-to-control asthma due to severe disease or poor adherence, severe allergies such as food allergies or history of anaphylaxis, previous severe life-threatening acute asthma, history of sudden severe unpredictable asthma flare-ups, or significant psychosocial factors).

Note: Assessments can be made by asking the same questions at each visit, or using validated questionnaires.

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

Good control Partial control Poor control

All of:

  • Daytime symptoms ≤2 days per week (lasting only a few minutes and rapidly relieved by rapid-acting bronchodilator)
  • No limitation of activities
  • No symptoms§ during night or when wakes up
  • Need for reliever# ≤2 days per week

Any of:

  • Daytime symptoms >2 days per week (lasting only a few minutes and rapidly relieved by rapid-acting bronchodilator)
  • Any limitation of activities*
  • Any symptoms during night or when wakes up††
  • Need for reliever# >2 days per week

Either of:

  • Daytime symptoms >2 days per week (lasting from minutes to hours or recurring, and partially or fully relieved by rapid-acting bronchodilator)
  • ≥3 features of partial control within the same week

† e.g. wheezing or breathing problems

‡ child is fully active; runs and plays without symptoms

§ including no coughing during sleep

# not including short-acting beta2 agonist taken prophylactically before exercise. (Record this separately and take into account when assessing management.)

* e.g. wheeze or breathlessness during exercise, vigorous play or laughing

†† e.g. waking with symptoms of wheezing or breathing problems

Note: Recent asthma control is based on symptoms over the previous 4 weeks. Each child’s risk factors for future asthma outcomes should also be assessed and taken into account in management.

Adapted from

Global Initiative for Asthma (GINA). Global strategy for the diagnosis and management of asthma in children 5 years and younger. GINA, 2009. Available from: http://www.ginasthma.org/

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Table. Sample questions for reviewing asthma in children

  • How many weeks does child’s reliever puffer last?
  • How often does child wheeze, become short of breath or cough?
  • Does child wake during the night due to wheezing, shortness of breath or coughing? (How many times per month?)
  • How often does child need to take reliever puffer? (How may puffs?)
  • Has child since last visit/ever needed to take oral corticosteroids? (How often and how much?)
  • Does child take a preventer puffer? (What dose? How many puffs per day?)
  • How often does child need new script for preventer medicine?
  • Has child missed time from childcare, school and or sport due to asthma?
  • How often does child get colds?
  • Is child using other medicines for respiratory symptoms (e.g. oral or intranasal antihistamines, intranasal corticosteroids)
  • How many weeks does child’s reliever puffer last?
  • [Specify time period, e.g. In the last year/month/2 weeks] how many times has child visited GP/hospital emergency room for asthma symptoms?

Note: Questions are a guide. Wording will depend on who is reviewing the child’s asthma.

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How this recommendation was developed

Consensus

Based on clinical experience and expert opinion (informed by evidence, where available).

Validated checklists or questionnaires can be used to assess recent asthma symptom control at each visit, e.g:

How this recommendation was developed

Consensus

Based on clinical experience and expert opinion (informed by evidence, where available).

If long-term treatment with high-dose inhaled corticosteroid is needed to control wheezing symptoms:

  • refer for specialist assessment (e.g. paediatric respiratory physician or paediatrician)
  • provide specific written advice (steroid alert card) for other health professionals such as emergency services (e.g. If child shows reduced consciousness, consider the possibility of adrenal insufficiency, check serum biochemistry, blood glucose level and serum cortisol urgently, and consider whether intramuscular hydrocortisone is indicated)
  • warn parents that adrenal suppression is a possible side effect and advise them what to do if the child develops symptoms consistent with adrenal insufficiency, such as lethargy, vomiting, abdominal pain or seizures (e.g. go to the emergency department without delay, tell staff that the child is using regular high-dose medicine for asthma, and hand them the child’s steroid alert card).

Table. Definitions of ICS dose levels in children

Inhaled corticosteroid

Daily dose (mcg)

Low

High

Beclometasone dipropionate

100–200

>200 (up to 400)

Budesonide

200–400

>400 (up to 800)

Ciclesonide

80–160

>160 (up to 320)

Fluticasone propionate

100–200

>200 (up to 500)

† Dose equivalents for Qvar (TGA-registered CFC-free formulation of beclometasone dipropionate)

‡ Ciclesonide is registered by the TGA for use in children aged 6 and over

Source

van Asperen PP, Mellis CM, Sly PD, Robertson C. The role of corticosteroids in the management of childhood asthma. The Thoracic Society of Australia and New Zealand, 2010. Available from: 
http://www.thoracic.org.au/clinical-documents/area?command=record&id=14

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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):

  • van Asperen et al. 2010 1
  • Zöllner et al. 2012 2
  • Ahmet et al. 2011 3
  • Priftis et al. 2008 4
  • Macdessi et al. 2003 5

Monitor linear growth (height and weight, accurately measured and plotted on a percentile chart) in children taking inhaled corticosteroids long term.

How this recommendation was developed

Adapted from existing guidance

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

  • van Asperen et al. 2010 1

More information

Classification of recent asthma symptom control in children

Ongoing review of asthma involves both assessing recent asthma symptom control and assessing risks for poor asthma outcomes (e.g. flare-ups, adverse effects of medicines).

Recent asthma symptom control is assessed according to the frequency of asthma symptoms over the previous 4 weeks.

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

Good control Partial control Poor control

All of:

  • Daytime symptoms ≤2 days per week (lasting only a few minutes and rapidly relieved by rapid-acting bronchodilator)
  • No limitation of activities
  • No symptoms§ during night or when wakes up
  • Need for reliever# ≤2 days per week

Any of:

  • Daytime symptoms >2 days per week (lasting only a few minutes and rapidly relieved by rapid-acting bronchodilator)
  • Any limitation of activities*
  • Any symptoms during night or when wakes up††
  • Need for reliever# >2 days per week

Either of:

  • Daytime symptoms >2 days per week (lasting from minutes to hours or recurring, and partially or fully relieved by rapid-acting bronchodilator)
  • ≥3 features of partial control within the same week

† e.g. wheezing or breathing problems

‡ child is fully active; runs and plays without symptoms

§ including no coughing during sleep

# not including short-acting beta2 agonist taken prophylactically before exercise. (Record this separately and take into account when assessing management.)

* e.g. wheeze or breathlessness during exercise, vigorous play or laughing

†† e.g. waking with symptoms of wheezing or breathing problems

Note: Recent asthma control is based on symptoms over the previous 4 weeks. Each child’s risk factors for future asthma outcomes should also be assessed and taken into account in management.

Adapted from

Global Initiative for Asthma (GINA). Global strategy for the diagnosis and management of asthma in children 5 years and younger. GINA, 2009. Available from: http://www.ginasthma.org/

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Inhaled corticosteroids for children: adverse effects

Topical

Hoarseness and pharyngeal candidiasis are not commonly reported among preschool children when using a metered-dose inhaler with spacer,6 or among school-aged children.1

Inhaled corticosteroids, particular dry-powder formulas with pH <5.5, may dissolve tooth enamel in children.1

Topical effects can be reduced by use of spacer devices (which reduce oropharyngeal deposition), and by mouth-rinsing and spitting after use.1 Immediate quick mouth-rinsing removes more residual medicine in the mouth than delayed rinsing.7

Systemic

Systemic effects of inhaled corticosteroids in children depend on the dose, but clinically significant adverse effects are uncommon.1 The use of spacers and mouth rinsing will not reduce systemic effects, but may increase efficacy so that a lower dose is required.

Short-term suppression of linear growth has been demonstrated in children, but only minimal long-term effects on growth or bone density have been reported.1 Some children may experience delay in the normal pubertal growth spurt due to asthma itself.1 Treatment beginning before puberty is associated with a small (mean approximately 1 cm) reduction in adult height.8

A research study using biochemical testing in a research setting showed that hypothalamic–pituitary–adrenal axis suppression may occur in up to two-thirds of children treated with inhaled corticosteroids, and may occur at even low doses.2 However, clinically cases are rare.

Cases of symptomatic, clinically significant adrenal insufficiency in children due to inhaled corticosteroid treatment have been reported,34 including cases in Australia.5 Most cases have involved children given more than 500 mcg per day fluticasone propionate.3

The risk of hypothalamic–pituitary–adrenal axis suppression is higher among children receiving concomitant intranasal steroids and those with lower body mass index.2 Risk is lower in obese children.2

There are no nationally accepted protocols for routine assessment of adrenal function because it has not yet been possible to identify precisely which children should be tested, to interpret test results reliably, to identify the appropriate interval for retesting, and because a clinical benefit has not been clearly demonstrated.

Table. Definitions of ICS dose levels in children

Inhaled corticosteroid

Daily dose (mcg)

Low

High

Beclometasone dipropionate

100–200

>200 (up to 400)

Budesonide

200–400

>400 (up to 800)

Ciclesonide

80–160

>160 (up to 320)

Fluticasone propionate

100–200

>200 (up to 500)

† Dose equivalents for Qvar (TGA-registered CFC-free formulation of beclometasone dipropionate)

‡ Ciclesonide is registered by the TGA for use in children aged 6 and over

Source

van Asperen PP, Mellis CM, Sly PD, Robertson C. The role of corticosteroids in the management of childhood asthma. The Thoracic Society of Australia and New Zealand, 2010. Available from: 
http://www.thoracic.org.au/clinical-documents/area?command=record&id=14

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Approaches to assessment and monitoring of asthma control in children

Assessment of asthma control in children is based mainly on recent asthma symptom control (assessed by the frequency and severity of symptoms between flare-ups and the degree to which asthma symptoms affect daily activities such as interference with physical activity or missed school days), the frequency of flare-ups, and spirometry in children who are able to perform the test reliably.

Parents commonly underestimate the severity of their child's asthma and overestimate asthma control.9

Standardised questionnaires

Questionnaire-based instruments have been validated for assessing asthma control in children:

Measures of airway inflammation

Measures of airway inflammation (e.g. sputum test, exhaled nitric oxide) are not used in clinical practice to guide treatment decisions. Tailoring the dose of inhaled corticosteroids based on exhaled nitric oxide appears to achieve only a small benefit in children, and may lead to higher doses.15 

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Correct use of inhaler devices

The majority of patients do not use inhaler devices correctly. Australian research studies have reported that only approximately 10% of patients use correct technique.1617

High rates of incorrect inhaler use among children with asthma and adults with asthma or COPD have been reported,18, 19, 20, 21, 22 even among regular users.23 Regardless of the type of inhaler device prescribed, patients are unlikely to use inhalers correctly unless they receive clear instruction, including a physical demonstration, and have their inhaler technique checked regularly.24

Poor inhaler technique has been associated with worse outcomes in asthma and COPD. It can lead to poor asthma symptom control and overuse of relievers and preventers.18, 25, 23, 26, 27 In patients with asthma or COPD, incorrect technique is associated with a 50% increased risk of hospitalisation, increased emergency department visits and increased use of oral corticosteroids due to flare-ups.23

Correcting patients' inhaler technique has been shown to improve asthma control, asthma-related quality of life and lung function.28, 29

Common errors and problems with inhaler technique

Common errors with manually actuated pressurised metered dose inhalers include:24

  • failing to shake the inhaler before actuating
  • holding the inhaler in wrong position
  • failing to exhale fully before actuating the inhaler
  • actuating the inhaler too early or during exhalation (the medicine may be seen escaping from the top of the inhaler)
  • actuating the inhaler too late while inhaling
  • actuating more than once while inhaling
  • inhaling too rapidly (this can be especially difficult for chilren to overcome)
  • multiple actuations without shaking between doses.

Common errors for dry powder inhalers include:24

  • not keeping the device in the correct position while loading the dose (horizontal for Accuhaler and vertical for Turbuhaler)
  • failing to exhale fully before inhaling
  • failing to inhale completely
  • inhaling too slowly and weakly
  • exhaling into the device mouthpiece before or after inhaling
  • failing to close the inhaler after use
  • using past the expiry date or when empty.

Other common problems include:

  • difficulty manipulating device due to problems with dexterity (e.g. osteoarthritis, stroke, muscle weakness)
  • inability to seal the lips firmly around the mouthpiece of an inhaler or spacer
  • inability to generate adequate inspiratory flow for the inhaler type
  • failure to use a spacer when appropriate
  • use of incorrect size mask
  • inappropriate use of a mask with a spacer in older children.

How to improve patients’ inhaler technique

Patients’ inhaler technique can be improved by brief education, including a physical demonstration, from a health professional or other person trained in correct technique.24 The best way to train patients to use their inhalers correctly is one-to-one training by a healthcare professional (e.g. nurse, pharmacist, GP, specialist), that involves both verbal instruction and physical demonstration.30, 18, 31, 32 Patients do not learn to use their inhalers properly just by reading the manufacturer's leaflet.31 An effective method is to assess the individual's technique by comparing with a checklist specific to the type of inhaler, and then, after training in correct technique, to provide written instructions about errors (e.g. a sticker attached to the device).16, 29

The National Asthma Council information paper on inhaler technique includes checklists for correct technique with all common inhaler types used in asthma or COPD.

Inhaler technique must be rechecked and training must be repeated regularly to help children and adults maintain correct technique.28, 18, 19 

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Steroid alert card

Written information (e.g. a steroid alert card) can be prepared for children receiving long-term high-dose inhaled corticosteroids. Parents can be instructed to present the card if the child ever needs to go to the emergency department (for any reason) or be admitted to hospital.

A steroid alert card should state that child has asthma and the inhaled corticosteroid dose.

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References

  1. van Asperen PP, Mellis CM, Sly PD, Robertson C. The role of corticosteroids in the management of childhood asthma. The Thoracic Society of Australia and New Zealand, 2010. Available from: http://www.thoracic.org.au/clinical-documents/area?command=record&id=14
  2. Zöllner EW, Lombard CJ, Galal U, et al. Hypothalamic-adrenal-pituitary axis suppression in asthmatic school children. Pediatrics. 2012; 130: e1512-19. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23147980
  3. Ahmet A, Kim H, Spier S. Adrenal suppression: A practical guide to the screening and management of this under-recognized complication of inhaled corticosteroid therapy. Allergy Asthma Clin Immunol. 2011; 7: 13. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3177893/
  4. Priftis KN, Papadimitriou A, Anthracopoulos MB, et al. Endocrine-immune interactions in adrenal function of asthmatic children on inhaled corticosteroids. Neuroimmunomodulation. 2009; 16: 333-9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19571594
  5. Macdessi JS, Randell TL, Donaghue KC, et al. Adrenal crises in children treated with high-dose inhaled corticosteroids for asthma. Med J Aust. 2003; 178: 214-6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12603184
  6. Brand PL, Baraldi E, Bisgaard H, et al. Definition, assessment and treatment of wheezing disorders in preschool children: an evidence-based approach. Eur Respir J. 2008; 32: 1096-1110. Available from: http://erj.ersjournals.com/content/32/4/1096.full
  7. 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
  8. Kelly HW, Sternberg AL, Lescher R, et al. Effect of inhaled glucocorticoids in childhood on adult height. N Engl J Med. 2012; 367: 904-12. Available from: http://www.nejm.org/doi/full/10.1056/NEJMoa1203229
  9. Carroll WD, Wildhaber J, Brand PL. Parent misperception of control in childhood/adolescent asthma: The room to breathe survey. Eur Respir J. 2011; 39: 90-96. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21700607
  10. Juniper EF, Gruffydd-Jones K, Ward S, Svensson K. Asthma Control Questionnaire in children: validation, measurement properties, interpretation. Eur Respir J. 2010; 36: 1410-6. Available from: http://erj.ersjournals.com/content/36/6/1410.long
  11. Murphy KR, Zeiger RS, Kosinski M, et al. Test for respiratory and asthma control in kids (TRACK): a caregiver-completed questionnaire for preschool-aged children. J Allergy Clin Immunol. 2009; 123: 833-9. Available from: http://www.jacionline.org/article/S0091-6749(09)00212-7/fulltext
  12. Zeiger RS, Mellon M, Chipps B, et al. Test for Respiratory and Asthma Control in Kids (TRACK): clinically meaningful changes in score. J Allergy Clin Immunol. 2011; 128: 983-8. Available from: http://www.jacionline.org/article/S0091-6749(11)01287-5/fulltext
  13. Liu AH, Zeiger R, Sorkness C, et al. Development and cross-sectional validation of the Childhood Asthma Control Test. J Allergy Clin Immunol. 2007; 119: 817-25. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17353040
  14. Liu AH, Zeiger RS, Sorkness CA, et al. The Childhood Asthma Control Test: retrospective determination and clinical validation of a cut point to identify children with very poorly controlled asthma. J Allergy Clin Immunol. 2010; 126: 267-73, 273.e1. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20624640
  15. Petsky HL, Cates CJ, Li A, et al. Tailored interventions based on exhaled nitric oxide versus clinical symptoms for asthma in children and adults. Cochrane Database Syst Rev. 2009; Issue 4: CD006340. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD006340.pub3/full
  16. Basheti IA, Armour CL, Bosnic-Anticevich SZ, Reddel HK. Evaluation of a novel educational strategy, including inhaler-based reminder labels, to improve asthma inhaler technique. Patient Educ Couns. 2008; 72: 26-33. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18314294
  17. Bosnic-Anticevich, S. Z., Sinha, H., So, S., Reddel, H. K.. Metered-dose inhaler technique: the effect of two educational interventions delivered in community pharmacy over time. The Journal of asthma : official journal of the Association for the Care of Asthma. 2010; 47: 251-6. Available from: https://www.ncbi.nlm.nih.gov/pubmed/20394511
  18. Price, D., Bosnic-Anticevich, S., Briggs, A., et al. Inhaler competence in asthma: common errors, barriers to use and recommended solutions. Respiratory medicine. 2013; 107: 37-46. Available from: https://www.ncbi.nlm.nih.gov/pubmed/23098685
  19. Capanoglu, M., Dibek Misirlioglu, E., Toyran, M., et al. Evaluation of inhaler technique, adherence to therapy and their effect on disease control among children with asthma using metered dose or dry powder inhalers. The Journal of asthma : official journal of the Association for the Care of Asthma. 2015; 52: 838-45. Available from: https://www.ncbi.nlm.nih.gov/pubmed/20394511
  20. Lavorini, F., Magnan, A., Dubus, J. C., et al. Effect of incorrect use of dry powder inhalers on management of patients with asthma and COPD. Respiratory medicine. 2008; 102: 593-604. Available from: https://www.ncbi.nlm.nih.gov/pubmed/18083019
  21. Federman, A. D., Wolf, M. S., Sofianou, A., et al. Self-management behaviors in older adults with asthma: associations with health literacy. Journal of the American Geriatrics Society. 2014; 62: 872-9. Available from: https://www.ncbi.nlm.nih.gov/pubmed/24779482
  22. Crane, M. A., Jenkins, C. R., Goeman, D. P., Douglass, J. A.. Inhaler device technique can be improved in older adults through tailored education: findings from a randomised controlled trial. NPJ primary care respiratory medicine. 2014; 24: 14034. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25188403
  23. Melani AS, Bonavia M, Cilenti V, et al. Inhaler mishandling remains common in real life and is associated with reduced disease control. Respir Med. 2011; 105: 930-8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21367593
  24. National Asthma Council Australia. Inhaler technique for people with asthma or COPD. National Asthma Council Australia, Melbourne, 2016. Available from: https://www.nationalasthma.org.au/living-with-asthma/resources/health-professionals/information-paper/hp-inhaler-technique-for-people-with-asthma-or-copd
  25. Bjermer, L.. The importance of continuity in inhaler device choice for asthma and chronic obstructive pulmonary disease. Respiration; international review of thoracic diseases. 2014; 88: 346-52. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25195762
  26. Haughney, J., Price, D., Barnes, N. C., et al. Choosing inhaler devices for people with asthma: current knowledge and outstanding research needs. Respiratory medicine. 2010; 104: 1237-45. Available from: https://www.ncbi.nlm.nih.gov/pubmed/20472415
  27. Giraud, V., Roche, N.. Misuse of corticosteroid metered-dose inhaler is associated with decreased asthma stability. The European respiratory journal. 2002; 19: 246-51. Available from: https://www.ncbi.nlm.nih.gov/pubmed/11866004
  28. Basheti IA, Reddel HK, Armour CL, Bosnic-Anticevich SZ. Improved asthma outcomes with a simple inhaler technique intervention by community pharmacists. J Allergy Clin Immunol. 2007; 119: 1537-8. Available from: http://www.jacionline.org/article/S0091-6749(07)00439-3/fulltext
  29. Giraud, V., Allaert, F. A., Roche, N.. Inhaler technique and asthma: feasability and acceptability of training by pharmacists. Respiratory medicine. 2011; 105: 1815-22. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21802271
  30. Basheti, I. A., Reddel, H. K., Armour, C. L., Bosnic-Anticevich, S. Z.. Counseling about turbuhaler technique: needs assessment and effective strategies for community pharmacists. Respiratory care. 2005; 50: 617-23. Available from: https://www.ncbi.nlm.nih.gov/pubmed/15871755
  31. Lavorini, F.. Inhaled drug delivery in the hands of the patient. Journal of aerosol medicine and pulmonary drug delivery. 2014; 27: 414-8. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25238005
  32. Newman, S.. Improving inhaler technique, adherence to therapy and the precision of dosing: major challenges for pulmonary drug delivery. Expert opinion on drug delivery. 2014; 11: 365-78. Available from: https://www.ncbi.nlm.nih.gov/pubmed/24386924