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St. Louis, MO
Dr. Tuteur is Associate Professor of Medicine, and Director, Pulmonary Function Laboratory, Washington University School of Medicine.
Correspondence to: Peter G. Tuteur, MD, FCCP, Pulmonary and Critical Care Division, Washington University School of Medicine, 660 South Euclid Ave, Campus Box 8052, St. Louis, MO 63110; e-mail: tuteurp{at}msnotes.wustl.edu
In this issue of CHEST (see page 1755), Kanazawa and colleagues observe that low levels of a biochemical marker in sputum of asthmatics change toward normal in response to the administration of inhaled corticosteroid (beclomethasone dipropionate [BDP]). They extend the observations to demonstrate a strong relationship of structure (albeit biochemical) and airways function. Since these markers presumably reflect inflammation, reversal in the sputum suggests improvement of the intraluminal inflammatory changes of asthma. Superficially, this is a good work. Read the abstract, comment on the connection of asthma to inflammation, and remember sputum peroxynitrite inhibitory activity (PNIA) for rounds tomorrow! But this is not the end of the story.
This work accomplishes much more because this translational clinical study fulfills a higher level of achievement. It is provocative at many levels. It promotes contemplation of questions—some old, some modified, some new. Hopefully, this response will lead to better understanding of the clinical problem, improved design of translational studies, and direction for basic pathogenic and pharmaceutical research.
The focused data of Kanazawa et al correlate the higher levels of oxidative products (nitrates and nitrites) found in the induced sputum of asthmatics with lower levels of an antioxidant marker, PNIA, compared with normal control subjects. They further demonstrate the reversal of these pertubations and parallel improvement of airways function (FEV1) in response to inhaled corticosteroids (BDP). What can this mean? Clearly, it provides even more support for the first-line use of inhaled corticosteroids in the treatment of asthma. The obvious reasoning is that asthma is, in part, characterized by airway inflammation, steroids are anti-inflammatory, markers of inflammation revert toward normal with BDP use, and airways function improves. But what are the implications of this substantial yet only partial reversal toward normal? Does that mean that a higher BDP dose is likely to provide even more functional improvement? Or, alternatively, is the reversal in response to inhaled steroids limited by factors unassociated with the drug action, per se? Is clinical response limited by drug distribution, complexity of molecular and cellular mechanism causing disease, or complications of the disease (ie, bacterial infection) not affected by BDP? Also, one might consider a situation when biochemical markers remain unchanged and abnormal in response to a standard dosage of inhaled corticosteroids. Does that mean that a higher dose is required? Or does this imply that alternative therapy must be considered possibly because inflammation is already maximally improved and that other mechanisms yielding an asthmatic phenotype are operative or remodeling has taken place? Or is the diagnosis wrong?
If one assumes that topical steroid deposited on airways will reduce/reverse the inflammation associated with asthma, then reasons for incomplete reversal may include inadequate dose, incomplete distribution of the agent due to failed delivery, heterogeneous distribution favoring larger over smaller airways, enhanced drug clearance in some areas minimizing its effect, inactivation of the agent by cellular or molecular factors active in the airways, or that the asthmatic phenotype as reflected by FEV1 measurements is complex and multifactorial in pathogenesis and steroids do not effect all pathways. These possibilities and others not mutually exclusive are testable. For example, if adequacy of a given dose is questioned, serial measurements of PNIA in induced sputum as dosage schedule is changed may aid the investigator and clinician to determine optimum dosage. If sputum PNIA determination is clinically cumbersome, measurements of exhaled nitric oxide could be evaluated as a surrogate. However, limitation of the use of markers in sputum to reflect all airway pathology is likely. Silkoff et al1 demonstrated that there was a disconnect between luminal vs submucosal inflammation when comparing sputum and BAL measurements with inflammation in airway biopsies. This raises questions of how observations in sputum may enhance or limit understanding. However, it is intriguing to query how this difference may be exploited to increase the power of a well-designed study.
Further consideration of this study leads to questions regarding the effect of remodeling of airways on the production of nitric oxides and PNIA.2 Further relationship of inflammation and remodeling, and the effect on airways function deserves inquiry.
Often presenting a clinical dilemma is the cause of inflammation. This raises the question: what is the effect of acute bacterial bronchitis or pneumonia on PNIA and nitric oxide markers among normal subjects as well as asthmatics? In these situations, do markers have diagnostic value, and/or can they be used to help follow the effect of antibiotics, and thus monitor therapeutic response?
It is the contemporary recommendation that persons with intermittent airways obstruction follow pulmonary function by regularly measuring peak flow, sometimes as often as four times daily to detect an early exacerbation and to help define when to intervene with rescue therapy.3 But the usefulness of peak flow is limited by its effort dependency, its reflection of function of larger (not smaller) airways, and its requirement for a willing and able subject of certain age. Can sputum markers of inflammation substitute for or enhance peak flow determinations? Can serial sputum PNIA levels detect worsening inflammation in a timely, effective, and efficient way? Can exhaled nitric oxide measurements more easily and rapidly provide similar information? Can such measurements, if considered useful in a research setting, be re-engineered to be user friendly and cost efficient in a clinical setting? Can these measurements help to differentiate the phenotype of bronchial reactivity to direct more successful therapeutic regimens as a function of etiology: viral, allergy, irritant? If not, why? If so, how?
Extending inquiry of marker use beyond the effect of standard therapeutic agents to the testing of newly designed drugs or modifications of old drugs is an obvious potential strategy. With utilization of PNIA, testing of a new inhaled steroid that requires bioactivation in the lung, or one of reduced particle size designed to deposit in smaller airways, may aid in the elucidation of structure and function relationships. Specifically, markers of extent of inflammatory inhibition (sufficiency of activation or extent of distribution) can in part help with direction for further refinement of the product. Designing new ligands that maintain efficacy in the airway and eliminate side effects is the goal. Objective structure and function testing using markers of inflammation may aid in its attainment.
Beyond drug design is the development of a model explaining the basis of airway immunity inflammation and remodeling in response to stimuli: allergen, virus, chemical irritant. Holtzman et al4 5 have postulated a "neoclassical" pathway depicting the role of the airway immune response in the development of asthmatic airways inflammation. They propose a complex mechanism of immune cell (T-cell) accumulation in the airways, the regulation of its behavior in the epithelial cell, and how viral infection leads to aberrant immune cell activation leading, under some circumstances, to chronic hyperreactivity and the asthma phenotype, presumably all under complex genetic control. A simple assessment of a single marker in airway secretions is not likely to lead to further refinements of the pathogenesis of asthma, but it may serve as a useful aid in some translational investigation.
Questions are stimulated by meaningful clinical observations. In part, this characteristic determines the value of a study. Good studies and good questions produce better understanding and better future studies.
References
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