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Asthma: The paradox of heterogeneity

2012; Elsevier BV; Volume: 129; Issue: 5 Linguagem: Inglês

10.1016/j.jaci.2012.03.026

1097-6825

Jeffrey M. Drazen,

Allergic Rhinitis and Sensitization

Discuss this article on the JACI Journal Club blog: www.jaci-online.blogspot.com. It seems so simple. A 25-year-old, otherwise healthy woman with a history of multiple visits to an emergency department for asthma treatment in her childhood is in your office. She vaguely remembers using an inhaler every day when she "was little" but does not remember much else about it. She had no problems with her breathing from age 12 years until a few months ago, when she started to note increasing shortness of breath during her spinning sessions at the gym. She was ignoring this problem but now that she has a cold,1Jackson D.J. Sykes A. Mallia P. Johnston S.L. Asthma exacerbations: origin, effect, and prevention.J Allergy Clin Immunol. 2011; 128: 1165-1174Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar she cannot sleep through the night because of wheeze and cough. Her history did not identify any environmental triggers, and the results of her skin test panel are negative. She has diffuse wheezes, her FEV1 is 60% of her predicted value, and with 2 puffs of albuterol, her FEV1 increases to 85% of her predicted value. She has asthma. Without further diagnostics, you start her on an inhaled glucocorticosteroid (ICS); the odds are 2 out of 3 in your favor2Sorkness C.A. Lemanske R.F. Mauger D.T. Boehmer S.J. Chinchilli V.M. Martinez F.D. et al.Long-term comparison of 3 controller regimens for mild-moderate persistent childhood asthma: the Pediatric Asthma Controller Trial.J Allergy Clin Immunology. 2007; 119: 64-72Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar, 3Malmstrom K. Rodriguez-Gomez G. Guerra J. Villaran C. Piñeiro A. Wei L.X. et al.Oral montelukast, inhaled beclomethasone, and placebo for chronic asthma.Ann Intern Med. 1999; 130: 487-495Crossref PubMed Scopus (587) Google Scholar that her symptoms will improve. You are right. Three weeks later, she is symptomatically back to normal, and her lung function is near normal. You have done well by her, but in your heart of hearts you know that something is missing. After years of treating patients with asthma, you know that this syndromic label means many different things.4Busse W.W. Asthma diagnosis and treatment: filling in the information gaps.J Allergy Clin Immunol. 2011; 128: 740-750Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar Asthma is a heterogeneous condition that, for the sake of first-line treatment, we have made homogenous. This is the paradox of heterogeneity. Asthmatic heterogeneity has been on caregivers' minds for nearly a century. In 1918, Francis Rackemann5Rackemann F.M. A clinical study of 150 cases of bronchial asthma.Boston Med Surg J. 1918; 178: 770-772Crossref Google Scholar described a series of 150 cases of bronchial asthma in the Boston Medical and Surgical Journal. He described extrinsic and intrinsic asthma, a classification still in use today, but there are lots of other kinds of asthmatic heterogeneity. Clinically, we also separate asthmatic patients by severity, with "severe asthma" thought to be a special category.6Barnes P.J. Severe asthma: advances in current management and future therapy.J Allergy Clin Immunol. 2012; 129: 48-59Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar However, there are also other ways to clinically classify asthma,4Busse W.W. Asthma diagnosis and treatment: filling in the information gaps.J Allergy Clin Immunol. 2011; 128: 740-750Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar such as exercise-induced, cold air–induced, and ozone-induced asthma. Over the years, we have also developed asthma classification schemes based on histologic phenotype, immune phenotype, genetic makeup, or treatment response.7Weiss S.T. New approaches to personalized medicine for asthma: where are we?.J Allergy Clin Immunol. 2012; 129: 327-334Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar For the past 2 decades, we have tried to bridge the gap between clinical presentation and disease biology.2Sorkness C.A. Lemanske R.F. Mauger D.T. Boehmer S.J. Chinchilli V.M. Martinez F.D. et al.Long-term comparison of 3 controller regimens for mild-moderate persistent childhood asthma: the Pediatric Asthma Controller Trial.J Allergy Clin Immunology. 2007; 119: 64-72Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar As detailed in the 7 articles that make up the "Asthma: current status and future directions" series, there have been some successes, but we still do not have a way to work up a given patient with asthma and to easily delineate the specific pathobiology that leads to her or his airway dysfunction. It is like treating infectious disease without a culture. We can recognize the clinical syndromes, but we cannot spell out the steps that lead from genetic or biochemical defects to disease presentation. There are hopes for asthma prevention,8Martinez F.D. New insights into the natural history of asthma: primary prevention on the horizon.J Allergy Clin Immunol. 2011; 128: 939-945Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar but none have been translated to practice. I think that the major reason for our failure to achieve the level of pathobiologic understanding needed to connect the dots from disease biology to clinical treatment is, paradoxically, the therapeutic efficacy of ICSs in asthmatic patients. ICSs are simply so effective that the bar for new entries is very high. Although there is a well-defined adverse effect profile for ICSs, the therapeutic benefit is overwhelming, and we have convinced ourselves and our patients not to worry. Thus the lack of effective treatments that has driven progress in many other areas of medicine is not compelling in the study of asthma. Perhaps we have been lulled into complacency because, different from hypertension or diabetes, where end points and consequences of failing to meet these end points are far more apparent and with bigger sequelae than in asthma, we have been happy to live with the favorable odds of an ICS response regardless of asthma phenotype. The problem with treating almost all patients with asthma with ICSs as first-line therapy9Expert Panel 3. Guidelines for the diagnosis and treatment of asthma. 7-1-2012.Google Scholar, 10GINA Science Committee. Global Initiative on Asthma. 12-1-2011. 3-15-2012.Google Scholar is that ICSs are not pathobiologically informative treatments. Paradoxically, in the 1980s, the mantra was that "asthma is an inflammatory disease and glucocorticoids are anti-inflammatory." Oh, if it were only that simple! This mantra suggested that ICS treatment was targeted at the inflammation seen in asthmatic patients. Consider that when the condition of a patient with cancer improves when treated with an inhibitor of signal transduction at the epidermal growth factor receptor, we can infer that the epidermal growth factor receptor was involved in the pathobiology of the treated cancer. When the condition of a patient with asthma improves when she is treated with an ICS, we learn nothing about the biology of her asthma. This is because ICSs have so many potential mechanisms of beneficial effects in asthmatic patients that improvement does not allow us to infer the mechanism of improvement. The lack of pathobiologically informative asthma therapy is not for lack of trying. For example, leukotriene modifiers were introduced in the 1990s; there has been some progress in identifying "leukotriene responders,"11Szefler S.J. Advancing asthma care: the glass is only half full!.J Allergy Clin Immunol. 2011; 128: 485-494Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar but their lack of predictive power has resulted in only limited pretreatment use. When "all comers" are treated with antileukotrienes, the overall therapeutic effect is about half of that observed when a similar group of asthmatic patients is treated with ICSs.3Malmstrom K. Rodriguez-Gomez G. Guerra J. Villaran C. Piñeiro A. Wei L.X. et al.Oral montelukast, inhaled beclomethasone, and placebo for chronic asthma.Ann Intern Med. 1999; 130: 487-495Crossref PubMed Scopus (587) Google Scholar Despite more than 15 years of experience with leukotriene modifiers, we do not have a way to predict in advance who will benefit from them. If we could a priori identify responders to treatment with reasonable surety, then this and perhaps other targeted medications could be used in a more directed fashion. As it is, research studies pursuing this end have not been successful.12Amlani S. Nadarajah T. McIvor R.A. Montelukast for the treatment of asthma in the adult population.Expert Opin Pharmacother. 2011; 12: 2119-2128Crossref PubMed Scopus (35) Google Scholar New information about asthma pathobiology was derived from research in animals and human subjects that was done in the past 2 decades.4Busse W.W. Asthma diagnosis and treatment: filling in the information gaps.J Allergy Clin Immunol. 2011; 128: 740-750Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 13Holgate S.T. Pathophysiology of asthma: what has our current understanding taught us about new therapeutic approaches?.J Allergy Clin Immunol. 2011; 128: 495-505Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar From this research, new targets, such as TNF-α, IL-5, and IL-13, were identified. Sadly, however, clinical trials with therapeutic agents targeting these pathways have not been rewarding. There is a recent ray of hope with the use of diagnostic tests to identify patients who might respond to anti–IL-13 therapy,14Corren J. Lemanske R.F. Hanania N.A. Korenblat P.E. Parsey M.V. Arron J.R. et al.Lebrikizumab treatment in adults with asthma.N Engl J Med. 2011; 365: 1088-1098Crossref PubMed Scopus (1304) Google Scholar but it is too early to know for sure whether this approach will be broadly applicable. I hope it is, but because I am from Missouri, you will have to "show me" with adequately designed and powered clinical trials. Does the failure of recent targeted treatments mean that the inferences of causality drawn from human and animal studies done over the past 20 years were incorrect? As outlined by Holgate13Holgate S.T. Pathophysiology of asthma: what has our current understanding taught us about new therapeutic approaches?.J Allergy Clin Immunol. 2011; 128: 495-505Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar in his article in this series, perhaps the paradigm that asthma is based on primary immune abnormalities that we have been pursuing for almost 2 decades needs to be revised. I agree. Perhaps the primary lesion in many forms of asthma is not inflammatory but rather at the level of the epithelium and its response to bronchoconstriction.15Tschumperlin D.J. Dai G. Maly I.V. Kikuchi T. Laiho L.H. McVittie A.K. et al.Mechanotransduction through growth-factor shedding into the extracellular space.Nature. 2004; 429: 83-86Crossref PubMed Scopus (266) Google Scholar, 16Grainge C.L. Lau L.C.K. Ward J.A. Dulay V. Lahiff G. Wilson S. et al.Effect of bronchoconstriction on airway remodeling in asthma.N Engl J Med. 2011; 364: 2006-2015Crossref PubMed Scopus (416) Google Scholar The genome-wide association studies that have been completed to date point to the epithelium as a primary player in the asthmatic diathesis.17Moffatt M.F. Gut I.G. Demenais F. Strachen D.P. Bouzigon E. Heath S. et al.A large-scale, consortium-based genomewide association study of asthma.N Engl J Med. 2010; 363: 1211-1221Crossref PubMed Scopus (1432) Google Scholar, 18Ober C. Nicolae D.L. Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations.Nat Genet. 2011; 43: 887-892Crossref PubMed Scopus (596) Google Scholar We should not ignore this. Perhaps the observed inflammation is the result of events rather that its cause? If true, this would turn our thinking on its head! Thus we are left with a paradox in the study of asthma. We have effective treatments that are not biologically informative, and we have informative treatments that are less effective. The cynic might say that most cases of asthma are multietiologic and thus ICSs are the perfect treatment. I disagree. What we need to do is make progress in understanding the root causes of asthma. For this, we need targeted diagnostics and therapeutics so we can infer causality and design the best treatment for each patient. The young woman with recurrent asthma who we met at the start of this editorial should receive a diagnosis and be treated in a directed and not haphazard fashion. If we fail to pursue this goal with vigor, the outlook for improved understanding of asthma biology and therefore its treatment is dismal. Our patients deserve better.