Asthma outcomes: Biomarkers

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Background

Measurement of biomarkers has been incorporated within clinical research studies of asthma to characterize the population and associate the disease with environmental and therapeutic effects.

Objective

National Institutes of Health institutes and federal agencies convened an expert group to propose which biomarkers should be assessed as standardized asthma outcomes in future clinical research studies.

Methods

We conducted a comprehensive search of the literature to identify studies that developed and/or tested asthma biomarkers. We identified biomarkers relevant to the underlying disease process progression and response to treatment. We classified the biomarkers as either core (required in future studies), supplemental (used according to study aims and standardized), or emerging (requiring validation and standardization). This work was discussed at an National Institutes of Health–organized workshop convened in March 2010 and finalized in September 2011.

Results

Ten measures were identified; only 1, multiallergen screening to define atopy, is recommended as a core asthma outcome. Complete blood counts to measure total eosinophils, fractional exhaled nitric oxide (Feno), sputum eosinophils, urinary leukotrienes, and total and allergen-specific IgE are recommended as supplemental measures. Measurement of sputum polymorphonuclear leukocytes and other analytes, cortisol measures, airway imaging, breath markers, and system-wide studies (eg, genomics, proteomics) are considered as emerging outcome measures.

Conclusion

The working group participants propose the use of multiallergen screening in all asthma clinical trials to characterize study populations with respect to atopic status. Blood, sputum, and urine specimens should be stored in biobanks, and standard procedures should be developed to harmonize sample collection for clinical trial biorepositories.

Section snippets

Summary

  • Atopic status is an important phenotype and should be documented in clinical research studies to permit adequate interpretation of study findings. The presence of allergen-specific IgE is a biomarker for atopic asthma.

  • The multiallergen screen is a single semiquantitative serologic measure of IgE against major allergens. It is considered a core biomarker that permits characterization of the atopic status of a study population in prospective clinical trials and observational studies. It

Cortisol

Cortisol measures can be used in the following ways:

  • Cortisol suppression measures are used primarily as a biomarker to assess inhaled or systemic corticosteroids with respect to the level of systemic exposure and their effect on the hypothalamic-pituitary-adrenal axis.

  • Measurement of cortisol levels (particularly 12-hour overnight or 24-hour plasma cortisol) should be considered for the characterization and definition of the therapeutic index of new corticosteroids (asthma effect-to-systemic

Biospecimen acquisition and storage for detection of biomarkers

Most clinical trials archive biospecimens for genetics and genomics (eg, transcriptomics, proteomics, lipomics, and metabolomics); however, the stability of the biospecimens over extended periods remains unclear. Generally, storage at −80°C immediately upon acquisition confers the greatest stability. Evidence suggests that samples obtained from study participants with asthma are more susceptible to degradation than those obtained from control participants.165, 166 Peripheral blood, the most

Priority questions for future research

  • 1.

    Can exhaled NO best be used as a unique marker of inflammation to predict and monitor response to asthma treatment?

  • 2.

    Do differences in sputum processing significantly affect the utility of sputum eosinophils to guide anti-inflammatory therapy?

  • 3.

    Can a simpler surrogate for sputum eosinophils be developed?

  • 4.

    Will characterization of asthma by atopic status contribute to a better understanding and differentiation of asthma phenotypes?

  • 5.

    What is the relationship between measures of cortisol suppression and

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    The Asthma Outcomes workshop was funded by contributions from the National Institute of Allergy and Infectious Diseases; the National Heart, Lung, and Blood Institute; the Eunice Kennedy Shriver National Institute of Child Health and Human Development; the National Institute of Environmental Health Sciences; the Agency for Healthcare Research and Quality; and the Merck Childhood Asthma Network, as well as by a grant from the Robert Wood Johnson Foundation. Contributions from the National Heart, Lung, and Blood Institute; the National Institute of Allergy and Infectious Diseases; the Eunice Kennedy Shriver National Institute of Child Health and Human Development; the National Institute of Environmental Health Sciences; and the US Environmental Protection Agency funded the publication of this article and all other articles in this supplement.

    Disclosure of potential conflict of interest: S. J. Szefler is a consultant for GlaxoSmithKline, Genentech, Merck, Boehringer-Ingelheim, Novartis, and Schering-Plough; and has received research support from the NIH (NHLBI, NIAID, NIEHS) and the Environmental Protection Agency. J. V. Fahy is on the Cytokinetics Scientific advisory board; has received consulting fees from Amgen, Gilcad, Five Prime Therapeutics, Merck, Regeneron Pharmaceuticals, Portola Pharmaceuticals; and has received research support from the NIH (NHLBI and NIAID) and Genentech. J. F. Hunt is on the Pulse Health LLC advisory board; is founder of Respiratory Research, Inc; has received research support from the NIH-NIAID and Altrea; and is Chair of the AAAAI Asthma Diagnosis and Pharmacotherapeutics Committee and Cough Committee. A. H. Liu has received speaker honoraria from Merck; is on the Data Safety Monitoring Board for GlaxoSmithKline; and is a consultant for DBV. R. A. Panettieri, Jr, is a consultant for Johnson & Johnson, Forest Pharmaceuticals, Genentech, and Merck; and has received research support from AstraZeneca, Johnson & Johnson, Merck, and Roche. R. P. Schleimer is a consultant for GlaxoSmithKline and Intersect ENT. The rest of the authors declare that they have no relevant conflicts of interest.

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