The Journal of Allergy and Clinical Immunology
Volume 124, Issue 6 , Pages 1186-1187, December 2009

New-onset mild asthma III: A sequel to 2 “Oscar winners”

  • Gene L. Colice, MD, FCCP

      Affiliations

    • Corresponding Author InformationReprint requests: Gene L. Colice, MD, FCCP, Washington Hospital Center, 110 Irving St, NW, Washington, DC 20010.

Pulmonary, Critical Care and Respiratory Services, Washington Hospital Center, George Washington University School of Medicine, Washington, DC

Received 29 October 2009; accepted 29 October 2009.

Article Outline

Key words: Asthma, inhaled corticosteroids, exacerbations, decline in lung function

 

Haahtela et al1, 2, 3 have performed a remarkable 3-part experiment in patients with new-onset, mild asthma that has now extended over a period of 13 years of follow-up. These investigators originally randomized 103 patients with new-onset, mild asthma to either budesonide or terbutaline treatment for 2 years.1 Patients treated with the inhaled corticosteroid (ICS) had better symptom, lung function, and bronchial hyperresponsiveness outcomes. They then performed a crossover study in a subset of these patients for a third year.2 Switching from a high to a lower dose of ICS was generally effective in maintaining stable asthma symptoms, lung function, and bronchial hyperresponsiveness, but patients switched from ICS to placebo did poorly. In patients initially on the short-acting inhaled β2-agonist, beginning an ICS resulted in improved asthma outcomes but possibly not as good an improvement as those begun on ICS initially. The authors suggested that delayed initiation of ICS might lead to an impaired response. Haahtela et al3 have most recently re-evaluated 90 of the original 103 patients (reported in this issue of the Journal). Treatment during the 13-year interval between the initial study and this re-evaluation was not controlled—that is, this was a real-life follow-up. At this re-evaluation, these patients would generally be classified, according to the Expert Panel Report 3, as well controlled.4 However, they still had exacerbations requiring hospitalization, and those patients requiring hospitalizations had a greater loss of lung function over time. Finally, there were subtle indications that the patients randomized to early ICS treatment in the initial study had better outcomes than those receiving the short-acting inhaled β2-agonist.

The real-life follow-up asthma care that these patients received must be appreciated in the context of how the initial work of Haahtela et al directly affected efforts to improve asthma care across Finland.5, 6 In 1993, the Finnish Ministry of Social Affairs and Health recognized asthma as an important health issue and initiated a comprehensive program throughout all structures of health care to address this problem. The steps taken in this program began at the national level, including legislation, development of guidelines and education materials, and advocacy by the Finnish Lung Health Association, but quickly spread to the regional level with emphasis on the role of the primary health care provider in providing asthma care. Key medical aspects of this program, directly derived from the results reported by Haahtela et al,1, 2 emphasized early ICS use to obtain remission of disease with longer-term treatment at reduced ICS doses to maintain efficacy. Implementation of this program led to widespread training of asthma coordinating physicians and nurses and availability of spirometry and educational materials. Most important was that this program led to a change in the overall culture of asthma care. Primary care providers, both physicians and nurses, took ownership of asthma care with reliance on specialists for only the more severe cases. Use of controller medication, particularly ICS, became more widespread. The initial goals of this program were ambitious but achievable. By 2004, statistics from Finland showed that asthma mortality had decreased, hospitalization days for asthma had fallen substantially, disability related to asthma was less of a problem, and average asthma costs were lower.5, 6

Observations in the most recent study by Haahtela et al3 compliment their earlier work by providing tantalizing insights into the relationship among asthma impairment, exacerbation risk, and change in lung function over time. Patients with asthma worry about asthma symptoms. They are appropriately concerned about being impaired in their ability to live a full and active life. The Expert Panel Report 3 includes as a goal for asthma management that impairment caused by asthma symptoms should be minimized.4 Well controlled asthma is explicitly defined as symptoms and need for rescue short-acting inhaled β2-agonist less than twice per week, minimal nighttime sleep disturbances, and normal lung function. Well controlled asthma is different, though, from totally controlled asthma, in which patients have no symptoms.7 Although the difference between symptoms less than twice per week and no symptoms might seem small, there may be more meaningful differences in terms of exacerbation risk. In a 1-year study addressing guideline-defined asthma control, patients with totally controlled asthma had an annualized severe exacerbation rate of 0.05, which was substantially lower than the rate of 0.13 for patients with well controlled asthma.7 Severe exacerbations, defined as those requiring oral corticosteroids, an emergency department visit, and/or hospitalization, are a concern because another clinical trial found that the lung function decline in patients with asthma over a period of 3 years was significantly greater in those with a severe exacerbation.8 Haahtela et al3 similarly found a clinically meaningful and statistically significant difference in lung function between those with and without recent hospitalizations for an asthma exacerbation (those without a recent hospitalization had a morning peak expiratory flow of 86.0% predicted vs 78.6% predicted for those recently hospitalized). These data suggest that with less than total control, there is an increased risk for both severe exacerbations and an accelerated decline in lung function over time. Using ICS to minimize exacerbation risk (and possibly reduce an accelerated decline in lung function over time) would require a reconsideration of our approach to ICS dosing adjustments. Studies using nontraditional approaches (methacholine responsiveness and sputum eosinophilia) to adjusting ICS doses in patients with asthma over time have shown that higher doses of ICS are required to minimize exacerbation risk than to simply manage symptoms.9, 10

Haahtela et al3 suggest in their latest report that early use of ICS in new-onset, mild asthma might affect airway inflammation in ways that extend through 13 years of follow-up. The group receiving ICS initially needed lower doses of ICS over time, had fewer asthma-related hospitalizations, and had less evidence of airway inflammation in induced sputum. Despite enormous advances in our understanding of the pathophysiology of airway inflammation in asthma, much is still unknown about the relationship between airway inflammation and asthma symptoms. For instance, airway inflammation is known to persist even in patients with asthma who are asymptomatic.11 It has also been observed that the clinical benefits of ICS do not persist after treatment has been stopped.12 These observations suggest that airway inflammation should be considered an ongoing problem in asthma. Unclear, though, is whether early ICS treatment, aggressively focused on eliminating airway inflammation entirely, followed by lower ICS dose maintenance therapy, might change the natural history of the disease. This possibility is suggested by 2 unusual aspects of the work by Haahtela et al. Initially, a high dose of budesonide was used.1 An ancillary study, relying on bronchoscopy biopsies in a small subset of patients, demonstrated that this approach successfully controlled airway inflammation.13

The first 2 parts of the trilogy by Haahtela et al1, 2 were critically acclaimed (“Oscar winners”). They played an instrumental role in influencing asthma care in Finland. By demonstrating the beneficial effects of early intervention with ICS, these clinical trial results improved real-life care of patients with asthma in Finland. The third installment is surely a box office success because it raises 2 provocative questions about our current approach to asthma care. If an accelerated decline in lung function in patients with asthma reflects more frequent severe exacerbations, ICS dosing adjustments over time should be made both to minimize impairment and to lower exacerbation risk substantially. If early treatment of new-onset asthma with ICS does influence the natural history of the disease, initial ICS dosing should be aggressive, intended to return the airway to normal, and followed by long-term lower-dose maintenance treatment.

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References 

  1. Haahtela T, Jarvinen M, Kava T, Kiviranta K, Koskinen S, Lehtonen K, et al. Comparison of a β2-agonist, terbutaline, with an inhaled corticosteroid, budesonide, in newly detected asthma. N Engl J Med. 1991;325:388–392
  2. Haahtela T, Jarvinen M, Kava T, Kiviranta K, Koskinen S, Lehtonen K, et al. Effects of reducing or discontinuing inhaled budesonide in patients with mild asthma. N Engl J Med. 1994;331:700–705
  3. Haahtela T, Tamminen K, Kava T, Malmberg LP, Rytila P, Nikander K, et al. Early intervention of asthma with an inhaled corticosteroid or a β2-agonist: a real-life follow-up 13 years later. J Allergy Clin Immunol. 2009;124:1180–1185
  4. National Asthma Education and Prevention Program. Expert Panel Report 3: guidelines for the diagnosis and management of asthma. Bethesda, Md: NHLBI; 2007;
  5. Haahtela T, Klaukka T, Koskela K, Erhola M, Laitinen LA. Asthma programme in Finland: a community problem needs community solutions. Thorax. 2001;56:806–814
  6. Haahtela T, Tuomisto LE, Pietinalho A, Klaukka T, Erhola M, Kaila M, et al. A 10 year asthma programme in Finland: major change for the better. Thorax. 2006;61:663–670
  7. Bateman ED, Boushey HA, Bousquet J, Busse WW, Clark TJH, Pauwels RA, et al. Can guideline-defined asthma control be achieved?. Am J Respir Crit Care Med. 2004;170:836–844
  8. O'Byrne PM, Pedersen S, Lamm CJ, Tan WC, Busse WW. Severe exacerbations and decline in lung function in asthma. Am J Respir Crit Care Med. 2009;179:19–24
  9. Sont JK, Willems LNA, Bel EH, van Kriekent JAJM, Vandenbroucke JP, Sterk PJ. Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment. Am J Respir Crit Care Med. 1999;159:1043–1051
  10. Green RH, Brightling CE, McKenna S, Hargadon B, Parker D, Bradding P, et al. Asthma exacerbations and sputum eosinophil counts: a randomized controlled trial. Lancet. 2002;360:1715–1721
  11. van den Toorn LM, Overbeek SE, de Jongste JC, Leman K, Hoogsteden HC, Prins JB. Airway inflammation is present during clinical remission of atopic asthma. Am J Respir Crit Care Med. 2001;164:2107–2113
  12. Strunk RC, Sternberg AL, Szefler SJ, Zieger RS, Bender B, Tonascia M, et al. Long-term budesonide or nedocromil treatment, once discontinued, does not alter the course of mild to moderate asthma in children and adolescents. J Pediatr. 2009;154:682–687
  13. Laitinen LA, Laitinen A, Haahtela T. A comparative study of the effects of an inhaled corticosteroid, budesonide, and a β2-agonist, terbutaline, on airway inflammation in newly diagnosed asthma. J Allergy Clin Immunol. 1992;90:32–42

 Disclosure of potential conflict of interest: G. Colice is an advisor, speaker, and consultant for Almirall, Forest, Teva, GlaxoSmithKline, Behringer Ingelheim, Pfizer, Schering Plough, and Lilly.

PII: S0091-6749(09)01628-5

doi:10.1016/j.jaci.2009.10.051

Refers to article:

  • Thirteen-year follow-up of early intervention with an inhaled corticosteroid in patients with asthma

    Tari Haahtela, Klaus Tamminen, Tuomo Kava, L. Pekka Malmberg, Paula Rytilä, Kurt Nikander, Tore Persson, Olof Selroos
    The Journal of Allergy and Clinical Immunology December 2009 (Vol. 124, Issue 6, Pages 1180-1185)

The Journal of Allergy and Clinical Immunology
Volume 124, Issue 6 , Pages 1186-1187, December 2009

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