Asthma Management Handbook

Conducting a treatment trial to confirm the diagnosis in children 0–5 years

Recommendations

For children over 12 months old with wheezing episodes that are associated with increased work of breathing (i.e. intercostal retraction), consider a trial of treatment with an inhaled short-acting beta2 agonist given as needed over a 48-hour period:

  • Show parents how to give salbutamol via a mask (infants) or spacer (pre-school children).
  • Tell parents to give 2–4 puffs (200–400 mcg) when child wheezes, and repeat if wheezing does not stop or recurs.
  • Ask parents to watch closely for whether child’s breathing becomes normal (i.e. child stops showing signs of increased work of breathing) and report effects.
How this recommendation was developed

Consensus

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

For children aged 6–12 months or less, consider a trial of treatment with as-need short-acting beta2 agonist, as for children over 12 months. Monitor closely and assess response, because asthma is less likely to be the cause of wheezing in this age group.

How this recommendation was developed

Consensus

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

For children under 6 months old, consider discussing with a paediatric respiratory physician or paediatrician before conducting a treatment trial with an inhaled short-acting beta2 agonist.

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):

  • Brand et al. 2008 1

If increased work of breathing resolves in response to inhaled bronchodilator (either during a treatment trial at home or observed in the clinic or hospital), this supports a provisional diagnosis of 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):

  • Brand et al. 2008 1

For children aged 12 months and over with a provisional diagnosis of asthma, consider a trial of preventer treatment if (either of):

  • wheezing episodes are accompanied by increased work of breathing and are severe enough to interrupt eating, play, physical activity or sleep
  • the child has been hospitalised due to acute wheezing and difficulty breathing.

Table. Initial preventer treatment for children aged 0–5 years

Age

Pattern of symptoms

Management options and notes *

0–12 months

Intermittent asthma

or

Viral-induced wheeze

Regular preventer treatment is not recommended

Multiple-trigger wheeze

Refer for specialist assessment or obtain specialist advice before prescribing

1–2 years

Intermittent asthma

or

Viral-induced wheeze

Regular preventer treatment is not recommended

Persistent asthma

or

Multiple-trigger wheeze

Consider a treatment trial with sodium cromoglycate 10 mg three times daily and review response in 2–4 weeks

Consider a treatment trial of low-dose inhaled corticosteroids only if wheezing symptoms are disrupting child’s sleeping or play; review response in 4 weeks

2–5 years

Infrequent intermittent asthma

or

Viral-induced wheeze

Regular preventer treatment is not recommended

Frequent intermittent asthma

or

Mild persistent asthma

or

Episodic (viral) wheeze with frequent symptoms

or

Multiple-trigger wheeze

Consider regular treatment with montelukast 4 mg once daily and review response in 2–4 weeks

If symptoms do not respond, consider regular treatment with a low dose of an inhaled corticosteroid and review response in 4 weeks

Moderate–severe persistent asthma

or

Moderate–severe multiple-trigger wheeze

Consider regular treatment with a low dose of an inhaled corticosteroid and review response in 4 weeks

  • Advise parents about potential adverse psychiatric effects of montelukast

* In addition to use of rapid-onset inhaled beta2 agonist when child experiences difficulty breathing

† Starting dose sodium cromoglycate 10 mg (two inhalations of 5 mg/actuation inhaler) three times daily. If good response, reduce to 10 mg twice daily when stable. Cromone inhaler device mouthpieces require daily washing to avoid blocking. 

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How this recommendation was developed

Consensus

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

If wheezing accompanied by increased work of breathing is markedly reduced during a treatment trial with a preventer, then recurs when treatment is stopped, this supports a provisional diagnosis of asthma in a preschool child. 

How this recommendation was developed

Consensus

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

Repeat the treatment trial if the effect on symptoms is unclear.

How this recommendation was developed

Adapted from existing guidance

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

  • Global Initiative for Asthma (GINA), 2009 2

Explain to parents that:

  • wheezing in the first few years of life does not mean the child will have asthma or allergies by primary school age
  • it is not possible to be certain that the child has asthma until he or she is old enough for objective lung function testing (spirometry) to assess whether lung function is excessively variable (i.e. demonstrate variable airflow limitation).
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):

  • Brand et al. 2008 1
  • Martinez et al. 1995 3 
  • Morgan et al. 2005 4
  • Henderson et al. 2008 5
  • Castro-Rodriguez, 2010 6

More information

Definition of wheeze

Wheeze is defined as a continuous, high-pitched sound coming from the chest during expiration.12 It is a non-specific sign caused by turbulent air flow due to narrowing of intrathoracic airways and indicates expiratory airflow limitation, irrespective of the underlying mechanism1 (e.g. bronchoconstriction or secretions in the airway lumen).

Inspiratory sounds (e.g. rattling or stridor) should not be described as ‘wheeze’.7

Various forms of noisy breathing, including wheezing, are common among babies and preschoolers.1 Noisy breathing is particularly common among infants under 6 months old, but only a small proportion have wheeze.1

Parents and doctors sometimes use the word ‘wheeze’ to mean different things,1, 7 including cough, gasp, a change in breathing rate or style of breathing. If based on parental report alone, children may be labelled as having wheeze when they do not have narrowed airways and expiratory flow limitation.1

There are no validated questionnaire-based instruments to identify wheeze in preschoolers,1 so wheezing is best confirmed by listening with a stethoscope during an episode.

Reported noisy breathing that responds to bronchodilator therapy is likely to be genuine wheeze and to be caused, at least in part, by constriction of airway smooth muscle.1

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Asthma versus wheezing disorder in children 0–5 years

Although many individuals later diagnosed with asthma first show respiratory symptoms by the age of 5 years,1 it is difficult to make the diagnosis of ‘asthma’ with a high degree of certainty in a baby or preschool child.

Some international guidelines1 avoid using the term ‘asthma’ for preschool children, because there is not enough evidence to know whether the pathophysiology of recurrent wheezing and asthma-like symptoms in preschool children is the same as that of asthma in older children and in adults,1 and because many young children with wheezing will not go on to develop asthma at school age.1 The more general term ‘wheezing disorder’ is sometimes used in preference to ‘asthma’ for children aged 5 years and under.1

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Classification of symptom patterns in children

The pattern and severity of symptoms in a child with asthma or wheezing disorder is a guide to initial treatment.

Table. Definitions of asthma patterns in children aged 0–5 years not taking regular preventer

Category

Pattern and intensity of symptoms (when not taking regular treatment)

Infrequent intermittent asthma

Symptom-free for at least 6 weeks at a time (flare-ups up to once every 6 weeks on average but no symptoms between flare-ups)

Frequent intermittent asthma

Flare-ups more than once every 6 weeks on average but no symptoms between flare-ups

Persistent asthma

Mild

At least one of:

  • Daytime symptoms more than once per week but not every day
  • Night-time symptoms more than twice per month but not every week

Moderate

Any of:

  • Daytime symptoms daily
  • Night-time symptoms more than once per week
  • Symptoms sometimes restrict activity or sleep

Severe

Any of:

  • Daytime symptoms continual
  • Night-time symptoms frequent
  • Flare-ups frequent
  • Symptoms frequently restrict activity or sleep

† Symptoms between flare-ups. A flare-up is defined as a period of worsening asthma symptoms, from mild (e.g. symptoms that are just outside the normal range of variation for the child, documented when well) to severe (e.g. events that require urgent action by parents and health professionals to prevent a serious outcome such as hospitalisation or death from asthma).

Note: Use this table when the diagnosis of asthma can be made with reasonable confidence (e.g. a child with wheezing accompanied by persistent cough or breathing difficulty, no signs or symptoms that suggest a potentially serious alternative diagnosis, and the presence of other factors that increase the probability of asthma such as family history of allergies or asthma).

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Table. Definitions of asthma patterns in children aged 6 years and over not taking regular preventer

Category

Pattern and intensity of symptoms (when not taking regular treatment)

Infrequent intermittent asthma †

Symptom-free for at least 6 weeks at a time (flare-ups up to once every 6 weeks on average but no symptoms between flare-ups)

Frequent intermittent asthma

Flare-ups more than once every 6 weeks on average but no symptoms between flare-ups

Persistent asthma

Mild

FEV1 ≥80% predicted and at least one of:

  • Daytime symptoms more than once per week but not every day
  • Night-time symptoms more than twice per month but not every week

Moderate

Any of:

  • FEV1 <80% predicted
  • Daytime symptoms daily
  • Night-time symptoms more than once per week
  • Symptoms sometimes restrict activity or sleep

Severe

Any of:

  • FEV1 ≤60% predicted
  • Daytime symptoms‡ continual
  • Night-time symptoms frequent
  • Flare-ups frequent
  • Symptoms frequently restrict activity or sleep

† It may not be appropriate to make the diagnosis of asthma in children aged 6 or older who wheeze only during upper respiratory tract infections. These children can be considered to have episodic (viral) wheeze.

‡ Symptoms between flare-ups. A flare-up is defined as a period of worsening asthma symptoms, from mild (e.g. symptoms that are just outside the normal range of variation for the child, documented when well) to severe (e.g. events that require urgent action by parents and health professionals to prevent a serious outcome such as hospitalisation or death from asthma).

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For children already taking regular preventer treatment, adjustments to the treatment regimen are based on finding the lowest dose of medicines that will maintain good control of symptoms.
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Short-term and long-term wheezing patterns in children: 0–5 years

Patterns of childhood wheezing over the short term

Classifying a child’s current pattern of symptoms can be useful for making immediate management decisions. The following descriptions of wheezing patterns apply to the pattern of symptoms in children aged 0–5 years and are sometimes used in clinical trials:

Episodic (viral) wheeze: episodes of wheezing (e.g. for a few days when child has a viral cold), but no wheezing between episodes.12

Multiple-trigger wheeze: episodes of wheezing from time to time, with cough and wheeze between episodes when child does not have a viral cold (e.g. when the child cries, plays or laughs).12

However, these patterns are not stable over time and have limited use in predicting whether or not a wheezing preschool child will have asthma by primary school age.89 An individual child is likely to show a different pattern within one year.8

Patterns of childhood wheezing over the long term

Longitudinal population-based cohort studies35 of preschool children with wheezing have identified various long-term patterns (wheezing phenotypes).1

Table. Systems for retrospectively classifying the duration of childhood wheeze

Classification system/source Phenotypes identified Description
Tucson Children’s Respiratory Study † ‡ Transient wheeze

Wheezing commences before the age of 3 years and disappear by age 6 years

Persistent wheeze

Wheezing continues until up to or after age 6 years

Late-onset wheeze

Wheezing starts after age 3 years.

Avon Longitudinal Study of Parents and Children § Transient early wheeze

Wheezing mainly occurs before 18 months, then mainly disappears by age 3.5 years

Not associated with hypersensitivity to airborne allergens

Prolonged early wheeze

Wheezing occurs mainly between age 6 months and 4.5 years, then mainly disappears before child’s 6th birthday

Not associated with hypersensitivity to airborne allergens

Associated with a higher risk of airway hyperresponsiveness and reduced lung function at age 8–9 years, compared with never/infrequent wheeze phenotype

Intermediate-onset wheeze

Wheezing begins sometime after age 18 months and before 3.5 years.

Strongly associated with atopy (especially house mite, cat allergen), higher risk of airway hyperresponsiveness and reduced lung function at age 8–9 years, compared with never/infrequent wheeze phenotype

Late-onset wheeze

Wheezing mainly begins after age 3.5 years

Strongly associated with atopy (especially house mite, cat allergen, grass pollen)

Persistent wheeze

Wheezing mainly begins after 6 months and continues through to primary school

Strongly associated with atopy

Notes

Terms can only be identified after the child has stopped wheezing for several years and cannot be applied to a preschool child.

Transient wheeze, persistent wheeze and late-onset wheeze can be episodic or multiple-trigger wheeze.#

Sources

† Martinez FD, Wright AL, Taussig LM et al. Asthma and wheezing in the first six years of life. The Group Health Medical Associates. N Engl J Med 1995; 332: 133-8. Available from: http://www.nejm.org/doi/full/10.1056/NEJM199501193320301#t=article

‡ Morgan WJ, Stern DA, Sherrill DL et al. Outcome of asthma and wheezing in the first 6 years of life: follow-up through adolescence. Am J Respir Crit Care Med 2005; 172: 1253-8. Available from: http://ajrccm.atsjournals.org/content/172/10/1253.long

§ Henderson J, Granell R, Heron J et al. Associations of wheezing phenotypes in the first 6 years of life with atopy, lung function and airway responsiveness in mid-childhood. Thorax 2008; 63: 974-80. Available from: http://thorax.bmj.com/content/63/11/974.long

# Brand PL, Baraldi E, Bisgaard H et al. Definition, assessment and treatment of wheezing disorders in preschool children: an evidence-based approach [European Respiratory Society Task Force]. Eur Respir J 2008; 32: 1096-110. Available from: http://erj.ersjournals.com/content/32/4/1096.full

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Early childhood wheezing phenotypes cannot be recognised or applied clinically, because they are recognised retrospectively.1 In an individual child with episodic wheeze, it is not possible to accurately predict epidemiological phenotype from clinical phenotype.1

Currently available tools for predicting whether a wheezing preschool child will have asthma at school age (e.g. the Asthma Predictive Index6) have limited clinical value.9

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Significance of wheeze in children 0–5 years

Approximately one in three children has at least one episode of wheezing before their third birthday,1 and almost half of all children have at least one episode of wheezing by age 6 years.1

Wheezing is the most common symptom associated with asthma in children aged 5 years and under.2 Among people with a diagnosis of asthma at any time in their life, approximately 80% will have shown signs of respiratory disease, such as wheezing, in the first years of life.6

However, the presence of wheeze does not mean a child has asthma or will develop asthma:

  • wheezing in infants up to 12 months old is most commonly due to acute viral bronchiolitis or to small and/or floppy airways
  • wheezing in children aged 1–5 years is usually associated with viral upper respiratory tract infections, which recur frequently in this age group.1, 2 Many children wheeze when they have viral respiratory infections, even if they do not have asthma2
  • among preschoolers with recurrent wheezing, only approximately one in three will have asthma at age 6 years6
  • wheezing can also be due to many conditions other than asthma, including anatomical abnormalities of the airways, cystic fibrosis, bronchomalacia.1
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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.1011

High rates of incorrect inhaler use among children with asthma and adults with asthma or COPD have been reported,12, 13, 14, 15, 16 even among regular users.17 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.18

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.12, 19, 17, 20, 21 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.17

Correcting patients' inhaler technique has been shown to improve asthma control, asthma-related quality of life and lung function.22, 23

Common errors and problems with inhaler technique

Common errors with manually actuated pressurised metered dose inhalers include:18

  • 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:18

  • 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.18 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.24, 12, 25, 26 Patients do not learn to use their inhalers properly just by reading the manufacturer's leaflet.25 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).10, 23

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.22, 12, 13 

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References

  1. 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
  2. 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/
  3. Martinez FD, Wright AL, Taussig LM, et al. Asthma and wheezing in the first six years of life. N Engl J Med. 1995; 332: 133-138. Available from: http://www.nejm.org/doi/full/10.1056/NEJM199501193320301#t=article
  4. Morgan WJ, Stern DA, Sherrill DL, et al. Outcome of asthma and wheezing in the first 6 years of life: follow-up through adolescence. Am J Respir Crit Care Med. 2005; 172: 1253-8. Available from: http://ajrccm.atsjournals.org/content/172/10/1253.long
  5. Henderson J, Granell R, Heron J, et al. Associations of wheezing phenotypes in the first 6 years of life with atopy, lung function and airway responsiveness in mid-childhood. Thorax. 2008; 63: 974-980. Available from: http://thorax.bmj.com/content/63/11/974.long
  6. Castro-Rodriguez JA. The Asthma Predictive Index: a very useful tool for predicting asthma in young children. J Allergy Clin Immunol. 2010; 126: 212-216. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20624655
  7. Weinberger M, Abu-Hasan M. Pseudo-asthma: when cough, wheezing, and dyspnea are not asthma. Pediatrics. 2007; 120: 855-864. Available from: http://pediatrics.aappublications.org/content/120/4/855.full
  8. Schultz A, Devadason SG, Savenije OE, et al. The transient value of classifying preschool wheeze into episodic viral wheeze and multiple trigger wheeze. Acta Paediatr. 2010; 99: 56-60. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19764920
  9. Savenije OE, Kerkhof M, Koppelman GH, Postma DS. Predicting who will have asthma at school age among preschool children. J Allergy Clin Immunol. 2012; 130: 325-331. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22704537
  10. 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
  11. 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
  12. 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
  13. 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
  14. 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
  15. 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
  16. 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
  17. 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
  18. 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
  19. 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
  20. 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
  21. 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
  22. 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
  23. 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
  24. 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
  25. 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
  26. 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