Divide and Conquer Opportunities for Individualized Treatment of Respiratory Disease
Divide and Conquer Opportunities for Individualized Treatment of Respiratory Disease
US Respiratory Disease 2006 - Issue II
Published: October 2008
Published: October 2008
Human respiratory disease is heterogeneous. As an example, recent data suggests that asthma in general, and severe asthma in particular, is not one disease, but a ‘syndrome’ into which several distinct disease processes have been grouped. Even cystic fibrosis (CF), a classic autosomal recessive disease, has a broad spectrum of clinical phenotypes.
Treatments do not uniformly benefit patients with conditions such as asthma and CF, and large numbers of patients are conventionally required to power therapeutic trials. It is important for healthcare providers to be familiar with evidence from large,wellpowered studies when evaluating therapeutic options for patients in these general classes of disease.
This principal has long been a cornerstone of modern medicine and has recently been codified as the doctrine of ‘evidence-based medicine’ (EBM).
Evidence-based Medicine versus Individual-based Medicine
The practical problem is that the patients we see in the office often do not fit an EBM mold. The exponential growth in genomic, proteomic, metabolomic, and modeling-based data, built on a foundation of comprehensive understanding of biochemistry, cell biology, and physiology, is now helping to begin to explain the heterogeneity of patients previously lumped into broad disease categories. These basic science insights are now leading to new, tailored therapeutic options. The growing tension between EBM and individual-based medicine is particularly evident in the case of several classes of respiratory disease.
Asthma
Asthma is one example. Expert panels have convened at the National Heart, Lung and Blood Institute to formulate precise guidelines for the management of asthma based on studies large enough to dampen signals arising from disease heterogeneity. The application of these guidelines has reduced asthma morbidity. In many cases, particularly including patients with severe asthma, these guidelines can subject patients to an unfavorable risk/benefit ratio. Recent work has argued that the science of asthma biology is ready to move beyond the current limits of classification and therapy.
Therapeutic Options
The biochemistry of asthmatic airway inflammation is diverse. This diversity is reflected in a spectrum of asthma phenotypes, and each phenotype implies a specific novel set of therapeutic options. Comhair et al. have shown that many patients with severe asthma have decreased serum activity of superoxide dismutase (SOD), and that those with low SOD activity have low forced expiratory volume in one second (FEV1). The relationship between SOD activity and FEV1 is not linear, some patients with severe asthma have substantially less SOD activity than others. The same group has shown that there is another subset of asthma patients with increased activity of the enzyme arginase associated with decreased FEV1.This increased activity deprives nitric oxide synthase (NOS) of substrate.
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