© 2007 American Thoracic Society doi: 10.1164/rccm.200703-302ED
If It Smells Like a Duck, It Might Be an Asthma SubphenotypeUniversity of Virginia, Charlottesville, Virginia Now beginning to be heard above the constant din of powerful marketing efforts to the converse, a growing wave of physicians have been shouting "asthma is not a diagnosis." Indeed, asthma is but a symptom, categorically on par with diarrhea. Imagine determining the optimum treatment strategy for diarrhea based almost entirely on whether it was "mild," "moderate," or "severe," and "intermittent" or "persistent." Imagine striving to control excessive stooling while neglecting to consider the cause. Imagine trying to study the genetics of diarrhea. Imagine attempting to examine the efficacy of a new drug by enrolling everyone with diarrhea, regardless of mechanism, in one giant study and expecting the results to be applicable to an individual patient. Now, what applies to diarrhea applies equally well, or equally poorly, to that symptom complex we still refer to as "asthma." Variable airway narrowing leading to wheeze can be caused by bronchospasm, inflammatory cell accumulation, mucous plugging, surfactant dysfunction, airway edema, airway vascular congestion, or abnormal structure and function of the airways (malacia, bronchiectasis). Each of these mechanisms of wheeze and air trapping has multiple underlying potential causes. It is no wonder that a one-size-fits-all strategy for managing asthma leaves many insufficiently diagnosed and wrongly treated, for many of the underlying mechanisms are left undiscovered or unaddressed. To optimize our therapeutic strategies, we are making increasing strides to seek the underlying causes for each individual patient's asthma using various tests. These efforts to subphenotype the patient's asthma are in effect efforts to make a true diagnosis. We determine whether or not inhalant allergies might be driving an inflammatory process. We try to guess if gastroesophageal reflux is a contributor to a patient's symptoms. We are starting to measure exhaled nitric oxide and induced sputum characteristics, thereby quantifying at least a small proportion of the myriad components of the nebulous entity known as inflammation, at which we otherwise blindly direct our therapies. These efforts are noteworthy. In this issue of AJRCCM (pp. 986–990), Carraro and colleagues (1) continue the efforts of an expanding contingent of researchers to develop means for acquiring biochemical information about the narrow and difficult-to-access passages that lead to our alveoli. They studied exhaled breath condensate—a body fluid easy to obtain (easy on patients), but difficult to assay (hard on scientists) (2). Using nuclear magnetic resonance (NMR) signals derived from concentrated exhaled breath condensate, Carraro and colleagues have identified NMR spectroscopy patterns that, at least post hoc, well differentiate patients with clinically identified asthma from control subjects. Although the human nose cannot sense these patterns, the magnetic nose can. Of course, how such high-tech testing as NMR spectroscopy of breath condensate compares to the gold-standard asthma diagnostic method can never be determined, for there is no gold-standard asthma diagnostic method—quite simply because asthma is not a diagnosis. These NMR signal patterns in exhaled breath condensate may not only serve as phenotypic discriminators but may also open a window on airway biochemical disturbances underlying airway cellular dysfunction. In other words, they may help us find the disease in each patient that leads to his or her asthma symptoms. We are moving down a path from DNA genomics, through RNA expression (gene chips), through proteomics, and now on to metabolomics. Each step down this path takes us closer to the direct cause of the physiologic disturbance (which, after all, is the part patients care about). In this preliminary, but novel, methodologic study, Carraro and colleagues speculate that the particular NMR chemical patterns they identify in patients with asthma symptoms may be attributable to abnormal acetylation and oxidation biochemistry of the asthmatic airway. Such chemical pathways are known to exist in humans (3), although their pathologic relevance in the lungs is completely unknown. As with many breath assays, dilution effects and oral contribution have not yet been well controlled, and prospective analysis based on the post hoc NMR patterns has not yet been done. But this study will be the first of many, and it may be that abnormal acetylation chemistry joins redox disturbance, airway acidification, and abnormal nitrosothiol chemistry as targets for new pharmacologic therapies aimed at addressing the metabolic disturbances of the airway. Noninvasive assays, such as NMR spectroscopic patterning of breath condensate, when validated sufficiently, can be anticipated to assist in identifying which patients are most likely to benefit from any such new therapies. Instead of testing oral antioxidants, inhaled alkaline buffers, and nitrosothiol supplementation as therapies for asthma, we can instead more appropriately test these compounds as specific treatments for "airway redox disturbance," "airway acidity," and "nitrosothiol deficiency," using the asthma symptoms as but one important outcome variable. In such a fashion, testing new therapeutic compounds can be performed in those patients having the relevant metabolic disturbance as identified with objective testing, as opposed to just seeing if the drug works in asthma. In a small way, airway metabolic abnormalities already have been used as the basis for therapeutic decisions, with some successes noted, such as the use of exhaled nitric oxide to minimize steroid dosing while maintaining symptom control (4). Identifying the more central metabolic disturbances that occur in the airway is now becoming possible. Validating noninvasive methods for studying lung metabolomics (far beyond just oxygen and carbon dioxide flux) seems a worthwhile pursuit. Exhaled breath condensate NMR is one new methodology showing promise. Like artificial nose technology and dogs that can sniff out cancer patients, NMR spectroscopy of breath samples provides an integrated signal pattern that can be recognized. After validation and standardization efforts are complete, breath NMR may allow us to say "this smells like allergic-driven eosinophilic asthma" with confidence that it actually does smell like it, as opposed to smelling like one of the many other causes underlying the several physiologic disturbances that can make a patient wheeze. Then, we as physicians can choose a course of therapy based on a confident diagnosis in each individual patient who has asthma symptoms, and perhaps relegate the severity-based asthma therapeutic guidelines to the history books, right beside the notion that asthma is a diagnosis. FOOTNOTES Conflict of Interest Statement: J.H. has received honoraria from Merck, research funding from Pfizer and GlaxoSmithKline, and is a cofounder of Respiratory Research, Inc., a developer of breath testing methodology. REFERENCES
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