Guidelines for Treatment of Asthma

29 

Guidelines for Treatment of Asthma: A Global Concern ALLAN BECKER

KEY POINTS • Guideline development is increasingly driven by published data (i.e. evidence based). • Guidelines increasingly focus on asthma control rather than severity. • Asthma control defines current ‘impairment’ and provides an indication of ‘future risk’ for an exacerbation. • For the young child with asthma there are limited published data to help direct recommendations for assessment and management strategies. • Implementation of guidelines is a major challenge which national or global guideline strategies and local champions can help to direct.

recommendations which were evolving within the expert group as a whole. Given the relative lack of research in children with asthma and a wide range of expert opinion on optimal approaches to treatment, the pediatricians were unable to develop any consensus focusing on the management of asthma in the pediatric population. However, over the next few years, pediatric-focussed guidelines began to emerge from national guideline committees with one of the earliest being from the British Thoracic Society9 in the mid-1990s. From that document, it became clear that separate categories and approaches to the diagnosis and management of asthma would be essential for school-aged children and for preschool children if the very best recommendations were to be developed. This was one of the first guidelines to bring focus to the issue of pediatric asthma, especially to recognition of the fact that there were few data upon which to build any recommended interventions for management of asthma in the young child.

Guideline Development

Evidence-Based Medicine

By the late 1980s, it was apparent that an epidemic of asthma had begun, particularly among children.1 This was emphasized by the dramatically increased mortality rates for asthma in New Zealand,2 which became the impetus for Australia and New Zealand to establish the first guidelines for the management of asthma in 1989.3 Shortly thereafter, consensus reports by expert panels on asthma assessment and management from Canada4 and from Britain5 were published as guidelines. This was followed shortly by the National Asthma Education and Prevention Program (NAEPP) Expert Panel Report from the USA in 1991.6 These early guidelines were based on expert opinion and provided consensus approaches to the diagnosis and management of asthma. The first international consensus report was coordinated by the National Heart Lung and Blood Institute (NHLBI) and published by the National Institutes of Health (NIH) in 1992.7 Subsequently, the NHLBI, in cooperation with the World Health Organization, launched the Global Initiative for Asthma (GINA) in 1993. The first GINA report was published by the NIH in 1995 as a ‘Global Strategy for Asthma Management and Prevention.’8 This was the first publication that aimed to provide a global approach to asthma and especially focussed on developing countries. As with previous guidelines, this was representative of expert opinion and consensus among those experts as to the best approach to asthma management. Each of the initial guidelines primarily focussed on asthma in adults. Exemplary of the problems with developing a consensus around asthma in childhood was the situation at the initial Canadian Consensus Conference in 1989. At that workshop, pediatricians met as a separate subgroup to discuss the 262

The development of the initial asthma guidelines was driven by expert opinion and these were consensus based. However, by the early 1990s it was recognized that it would be important to define the quality of data and to begin to focus on evidencebased recommendations. Unfortunately, as evidenced by the very carefully structured British Thoracic Society guidelines, when an attempt was undertaken to rigorously define the quality of evidence for management of asthma in children, the best available evidence for pediatric asthma remained at the lowest level of quality (i.e. expert opinion generating a consensus).9 The levels of evidence used in a number of guidelines, including the GINA strategy and the NAEPP guidelines, are shown in Table 29-1. This approach still underpins current GINA and NAEPP recommendations, including those recommendations for children. Although the initial pediatric guideline recommendations reflected expert opinion, an important outcome was the recognition that there was a substantial lack of data to help guide recommendations for the management of children with asthma. As a result, a key component of the first Canadian Pediatric Asthma Guidelines10 published in 2005 was a section entitled ‘Implications for Research.’ This important component of a number of national guidelines was a stimulus toward promoting research in children and recognizes in particular that the development of the majority of cases of asthma begins in the preschool years11 (Figure 29-1). Increasing research in childhood asthma was important in facilitating development of the National Heart Lung and Blood Institute National Education Prevention Program Expert Panel Report 3: Guidelines for the diagnosis and management of



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TABLE 29-1 

Evidence Level

Sources of Evidence

Definition

A

Randomized controlled trials (RCTs) and meta-analyses Rich body of data

B

RCTs and meta-analyses Limited body of data

C

Non-randomized trials Observational studies Panel consensus judgment

Evidence is from end-points of well-designed RCTs or meta-analyses that provide a consistent pattern of findings in the population for which the recommendation is made Category A requires substantial numbers of studies involving substantial numbers of participants Evidence is from end-points of intervention studies that include only a limited number of patients, post hoc or subgroup analysis of RCTs or meta-analysis of such RCTs In general, Category B pertains when few randomized trials exist, they are small in size, they were undertaken in a population that differs from the target population of the recommendation, or the results are somewhat inconsistent Evidence is from outcomes of uncontrolled or non-randomized trials or from observational studies This category is used only in cases where the provision of some guidance was deemed valuable, but the clinical literature addressing the subject was insufficient to justify placement in one of the other categories The Panel Consensus is based on clinical experience or knowledge that does not meet the criteria listed above

D

Incidence rates/100 0000

4000 Females Males 3000

2000

1000

0

<1

1-4

5-9 10-14 15-29 Age group (years)

30-49

>50

Figure 29-1  Annual incident rates per 100,000 person-years by sex and range for definite + probable asthma cases among Rochester residents 1964–1983. (Data from Yunginger JW, Reed CE, O’Connell EJ, Melton LJ 3rd, O’Fallon WM, Silverstein MD. A community-based study of the epidemiology of asthma. Incidence rates, 1964–1983. Am Rev Respir Dis 1992;146(4):888–94.)

organizations which are pertinent to their specific population characteristics, available healthcare resources and local or national environments. Guidelines are commonly developed by a panel of experts where the intent is to produce recommendations based on the best evidence available. Increasingly, there are pressures to produce recommendations based on the quality of a body of evidence assessed independently by a multidisciplinary team. Increasing adherence and focus to better define the quality of evidence remains a problem where there is a lack of substantive data. This is most apparent in the assessment and management of asthma in children during the preschool years. We require substantially more research in this area, both more structured randomized controlled trials and improved observational studies. Until such data are more abundant, guideline recommendations for the young child will continue to rest on expert panels with the appropriate clinical experience to provide the best possible recommendations for consideration in the development of local and national guidelines.

Asthma Severity and Control 12

asthma published in 2007. In that report, there was a strong focus on asthma in the preschool years (children 0–4 years of age) and in school-age children (5–11 years of age). Although there has been more research relating to asthma and the young child over the past decade, data to substantially update guidelines for children with asthma during the preschool years remain limited. In 2008, GINA approached the issue of asthma in the young child and established a panel of pediatric asthma experts to focus on the issues of concern in these young, preschool children. In 2009, GINA published the ‘Global Strategy for Asthma Management and Prevention in Children 5 Years and Younger’ with an emphasis on challenges in the diagnosis and management of asthma in these preschool children.13 Recommendations in the report were based on the best evidence available. However, because of the relative paucity of randomized or even observational clinical trials in this population, many recommendations remained at level D, i.e. panel consensus judgment. The expert opinion approach based on available data and consensus opinion published by GINA provides a strategy for the development of guidelines by local and national

Initially, most asthma guidelines focussed on defining levels of asthma severity. However, conceptually to guidelines developers, and of particular importance to patients with asthma and their families, asthma control is a far more important focus. As the focus in guideline development shifted to assessment of asthma control, it became increasingly apparent that asthma control should be considered within two distinct domains: symptom control, which can be considered to represent the current level of ‘impairment’, and ‘future risk’ for asthma worsening or exacerbation. These domains are now well recognized and are regularly an important component of guidelines. As noted in the previous edition of this textbook, ‘Impairment is the assessment of the frequency and intensity of symptoms as well as the functional limitations that the patient is experiencing now or in the past because of his or her asthma. Risk is the estimate of the likelihood of an asthma exacerbation, progressive loss of pulmonary function over time caused by asthma, or an adverse event from medication or even death. The assessment of severity and control provide guidance on the direction taken, stepping up or stepping down medications.’14

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TABLE 29-2 

SECTION F  Asthma

GINA Assessment of Asthma Control in Children 5 Years and Younger

One example of asthma control parameters is the GINA 2014 assessment of asthma control for children 5 years and younger (Table 29-2).15 For older children, the additional measurement of forced expiratory volume in 1 second (FEV1) contributes to a better understanding of the risk factors for future asthma control. Whenever possible, pulmonary function should be a routine component of asthma assessments.

Management of Asthma for Children Asthma therapy must take into consideration the level of asthma symptom control (i.e. impairment) and future risk. In schoolage children, this tends to be rather more straightforward than in the preschool child with recurrent wheezing episodes and a less certain asthma diagnosis. Although ‘not all that wheezes is asthma’, much of what wheezes or has severe, paroxysmal cough is treated as asthma. While there is increasing recognition of the heterogeneity of asthma phenotypes at all ages, management of wheezing syndromes in early life is a particular problem. Many children with asthma during the preschool years have only infrequent episodes of viral-induced wheezing and few, if any, interval symptoms. However, even if infrequent, these wheezing episodes can be quite severe. Thus, symptom frequency and severity are not equally matched. The optimal management of these children remains a concern to many healthcare professionals. In addition, in many countries, there are limited ‘approved’ medications for use in this population. This is a problem in a population most in need of research but difficult to study in large part because of the lack of objective outcome

parameters. As a result, ‘expert opinion’ and general consensus remain the core of most recommendations. Further, this is a population in which long-term adverse effects of most interventions remain poorly studied. For school-age children, the approach to management remains similar to that for the adolescent and adult populations. Figure 29-2 from the most recent GINA Global Strategy for Asthma Management and Prevention, revised 2014, provides treatment recommendations for the preschool child with asthma.15 It is representative of a ‘typical’ approach to management of asthma in the young child based on the available data (often extrapolated from studies in older children) as interpreted by ‘asthma experts’. Regardless of the pharmacological approach to the management of asthma, all guidelines continue to support the importance of education for children and their families.

Have Guidelines Benefitted Children and Their Families? Although the appraisal of guidelines, research and evaluation (AGREE) process defines the quality of asthma guidelines to be ‘low’, asthma guidelines do continue to improve.16 A recent editorial questioned whether practice guidelines are of any benefit to patients.17 After all, benefits to children and their families should be the primary objective for framing pediatric guideline development. The author of that editorial suggested that ‘Published guidelines are therefore not an adequate



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AS SE S

E NS

S

Asthma medications Non-pharmacological strategies Treat modifiable risk factors M

EN

T

Symptoms Exacerbations Side-effects Parent satisfaction

REVIEW R ES PO

Diagnosis Symptom control & risk factors Inhaler technique & adherence Parent preference

E A DJ U ST T R

AT

STEP-4 STEP-3 STEP-1 PREFERRED CONTROLLER CHOICE

Daily low-dose ICS Leukotriene receptor antagonist (LTRA) intermittent ICS

Other controller options

Double ‘low-dose’ ICS Low dose ICS + LTRA

Continue controller & refer for specialist assessment Add LTRA Inc. ICS frequency Add intermittent ICS

As-needed short-acting β2-agonist (all children)

RELIEVER

CONSIDER THIS STEP FOR CHILDREN WITH:

STEP-2

Infrequent viral wheezing and no or few interval symptoms (Box 6-2)

Symptom pattern consistent with asthma (Box 6-2) and asthma symptoms not well-controlled (Box 6-4), or ≥3 exacerbations per year

Asthma diagnosis, and not well-controlled on low-dose ICS

Symptom pattern not consistent with asthma (Box 6-2) but wheezing episodes occur frequently, e.g. every 6–8 weeks Give diagnostic trial for 3 months

First check diagnosis, inhaler skills, adherence, exposures

Not well-controlled on double ICS

ALL CHILDREN KEY ISSUES

• • • •

Assess symptom control, future risk (Box 6-4), co-morbidities Self-management: education, inhaler skills, written asthma action plan, adherence Regular review: assess response, adverse events, establish minimal effective treatment (Where relevant): environmental control for smoke, allergens, indoor/outdoor air pollution

ICS: inhaled corticosteroid; intermitt: intermittent. See Box 6-6 for definition of ‘low-dose’ ICS in children 5 years and younger.

Figure 29-2  Stepwise approach to long-term management of asthma in children aged 5 years and younger.

substitute for actual successful clinical experience by specialists during residency.17 Although this is not a simple issue, it may be particularly important for young children, and the concerns raised in that editorial must be addressed. Development of guidelines is typically followed by widespread dissemination of a document, usually with substantial documentation as to the quality of recommendations. As previously noted, ‘Of necessity to establish the quality, or weight, of the recommendations, the documents must present data and… the quality and depth of

material also supports the likelihood of publication to enable these primary dissemination approaches.’18 These ‘weighty’ documents are frequently translated into shortened summary publications and often one- or two-page pocket guides are developed which can be particularly helpful to trainees and primary care physicians. While dissemination is generally considered to be straightforward, implementation of guidelines has been a major concern, particularly at the local level. There have been a

266

SECTION F  Asthma

number of studies aimed at improving adherence to asthma guidelines. A recent systematic review demonstrated that use of decision support tools with feedback on audit and support from a clinical pharmacy were the most likely approaches to improve provider adherence to asthma guidelines.19 However, even with complicated and expensive interventions, only a limited number of studies have been associated with an improvement in healthcare status.19 A recent review asked ‘Have expert guidelines made a difference in asthma outcomes?’20 That review, which considered both controlled and observational trials, was unable to demonstrate substantive impact on health outcomes and noted that we need to ‘better understand the gaps between guidelines recommendations and translation to clinical practice… to improve asthma outcomes.’20 Nevertheless, there are studies, such as one from Costa Rica, that demonstrate

substantive impact with decreasing trends in hospitalization and mortality from asthma after institution of a national asthma program.21 The quality of asthma guidelines has improved over time.16 It is increasingly clear that guidelines are important in order to provide the best available data combined with advice based on expert opinion. However, to be of benefit to patients and their families, adaptation and implementation of guidelines must be undertaken at national and, possibly even better, at local levels, and supported by local champions with appropriate stakeholder involvement.22 The complete reference list can be found on the companion Expert Consult website at http://www.expertconsult.inkling .com.

KEY REFERENCES 2. Jackson RT, Beaglehole R, Rea HH, Sutherland DC. Mortality from asthma: a new epidemic in New Zealand. Br Med J 1982;285:771–4. 3. Woolcock A, Rubinfeld AR, Seale JP, Landau LL, Antic R, Mitchell C, et al. Thoracic society of Australia and New Zealand. Asthma management plan, 1989. Med J Aust 1989;151: 650–3. 7. International consensus report on diagnosis and treatment of asthma. National heart, lung, and blood institute, national institutes of health. Bethesda, Maryland 20892. Publication no. 92-3091, March 1992. Eur Respir J 1992;5: 601–41.

9. British Thoracic Society. The British guidelines on asthma management; 1995 review and position statement. Thorax 1997;52: S1–21. 10. Becker A, Berube D, Chad Z, Dolovich M, Ducharme F, D’Urzo T, et al. Canadian Pediatric Asthma Consensus guidelines, 2003 (updated to December 2004): introduction. CMAJ 2005; 173(Suppl. 6):S12–14. 11. Yunginger JW, Reed CE, O’Connell EJ, Melton LJ 3rd, O’Fallon WM, Silverstein MD. A community-based study of the epidemiology of asthma. Incidence rates, 1964–1983. Am Rev Respir Dis 1992;146:888–94.

12. National Institutes of Health. National Heart, Lung and Blood Institute. National asthma education and prevention program: expert panel report 3: guidelines for the diagnosis and management of asthma. NIH; 2007. 13. Global Initiative for Asthma. Global strategy for asthma management and prevention. 2009. Available from www.ginasthma.org. 15. Global Initiative for Asthma. Global strategy for asthma management and prevention. 2014. Available from www.ginasthma.org. 20. Podjasek JC, Rank MA. Have expert guidelines made a difference in asthma outcomes? Curr Opin Allergy Clin Immunol 2013;13:237–43.

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REFERENCES 1. Manfreda J, Becker AB, Wang PZ, Roos LL, Anthonisen NR. Trends in physician-diagnosed asthma prevalence in Manitoba between 1980 and 1990. Chest 1993;103:151–7. 2. Jackson RT, Beaglehole R, Rea HH, Sutherland DC. Mortality from asthma: a new epidemic in New Zealand. Br Med J 1982;285:771–4. 3. Woolcock A, Rubinfeld AR, Seale JP, Landau LL, Antic R, Mitchell C, et al. Thoracic society of Australia and New Zealand. Asthma management plan, 1989. Med J Aust 1989;151:650–3. 4. Hargreave FE, Dolovich J, Newhouse MT. The assessment and treatment of asthma: a conference report. J Allergy Clin Immunol 1990;85: 1098–111. 5. Guidelines for management of asthma in adults: I – Chronic persistent asthma. Statement by the British Thoracic Society, Research Unit of the Royal College of Physicians of London, King’s Fund Centre, National Asthma Campaign. BMJ 1990;301:651–3. 6. Guidelines for the diagnosis and management of asthma. National heart, lung, and blood institute. National asthma education program. Expert Panel Report. J Allergy Clin Immunol 1991;88(3 Pt 2):425–534. 7. International consensus report on diagnosis and treatment of asthma. National heart, lung, and blood institute, national institutes of health. Bethesda, Maryland 20892. Publication no. 92-3091, March 1992. Eur Respir J 1992;5: 601–41.

8. National Heart, Lung and Blood Institute and World Health Organization. Global initiative for asthma. NIH; 1995. 9. British Thoracic Society. The British guidelines on asthma management; 1995 review and position statement. Thorax 1997;52:S1–21. 10. Becker A, Berube D, Chad Z, Dolovich M, Ducharme F, D’Urzo T, et al. Canadian Pediatric Asthma Consensus guidelines, 2003 (updated to December 2004): introduction. CMAJ 2005; 173(Suppl. 6):S12–14. 11. Yunginger JW, Reed CE, O’Connell EJ, Melton LJ 3rd, O’Fallon WM, Silverstein MD. A community-based study of the epidemiology of asthma. Incidence rates, 1964–1983. Am Rev Respir Dis 1992;146:888–94. 12. National Institutes of Health. National Heart, Lung and Blood Institute. National asthma education and prevention program: expert panel report 3: guidelines for the diagnosis and management of asthma. NIH; 2007. 13. Global Initiative for Asthma. Global strategy for asthma management and prevention. 2009. Available from www.ginasthma.org. 14. Szefler S. Guidelines for the treatment of childhood asthma: gains and opportunities. In: Leung DYM, Sampson HA, Geha R, Szefler SJ, editors. Pediatric allergy: principles and practice. 2nd ed. Mosby; 2011. 15. Global Initiative for Asthma. Global strategy for asthma management and prevention. 2014. Available from www.ginasthma.org.

16. Acuna-Izcaray A, Sanchez-Angarita E, Plaza V, Rodrigo G, Montes de Oca M, Gich I, et al. Quality assessment of asthma clinical practice guidelines: a systematic appraisal. Chest 2013; 144:390–7. 17. Weinberger M. NHLBI asthma guidelines: no benefit for patients? Pediatr Pulmonol 2012; 47:632–4. 18. Becker A. Pediatric asthma guidelines: what are they good for? A view from the ‘pro’ side. Pediatr Pulmonol 2012;47:629–31. 19. Okelo SO, Butz AM, Sharma R, Diette GB, Pitts SI, King TM, et al. Interventions to modify health care provider adherence to asthma guidelines: a systematic review. Pediatrics 2013; 132:517–34. 20. Podjasek JC, Rank MA. Have expert guidelines made a difference in asthma outcomes? Curr Opin Allergy Clin Immunol 2013;13:237–43. 21. Soto-Martinez M, Avila L, Soto N, Chaves A, Celedon JC, Soto-Quiros ME. Trends in hospitalizations and mortality from asthma in Costa Rica over a 12- to 15-year period. J Allergy Clin Immunol Pract 2014;2:85–90. 22. Boulet LP, FitzGerald JM, Levy ML, Cruz AA, Pedersen S, Haahtela T, et al. A guide to the translation of the Global Initiative for Asthma (GINA) strategy into improved care. Eur Respir J 2012;39:1220–9.