Vol. 13 •Issue 4 • Page 18
Allergy & Asthma
New Diagnostic Approaches Offer Views to Asthma’s Inflammatory Process
Clinical investigators are developing diagnostic tools that provide a noninvasive window into the source of asthma patients’ breathlessness: the inflammatory process.
In recent years, respiratory clinicians’ understanding of asthma has undergone a metamorphosis of sorts. Asthma is now classified as a chronic inflammatory disorder of the airways.
Specialized cells such as mast cells, eosinophils, T lymphocytes, neutrophils and epithelial cells play a critical role in translating a stimulus (allergen, cold air and exercise) into a biochemical event. The result is the constellation of symptoms seen in so many asthma patients, including wheezing, early morning or late-night cough, thick sputum production, and shortness of breath.
The basic data sources we traditionally have relied on to confirm a suspicion of asthma — a detailed history, physical exam, chest X-ray, allergy testing, methacholine challenge tests and spirometry — may be complemented by new approaches that bring us closer to asthma’s root cause.
The current thinking in asthma management is that challenge testing, the administration of aerosols to the airway to measure hyperreactivity of the airway, is directly correlated with airway inflammation. Methacholine, a parasympathomimetic, is typically used for this purpose. For many patients, inhaled corticosteroids will substantially reduce the responsiveness to the methacholine challenge.
Now, evidence supports the notion that adenosine may be an alternative to methacholine for challenge testing. Methacholine exerts its effect on the airway directly, causing the smooth muscle to contract. Adenosine takes a more indirect path; it activates receptors on mast cells in the airway, which in turn release histamine and other mediators to produce smooth airway contraction. Studies suggest that the biochemical cascade produced by adenosine correlates better with traditional markers of inflammation such as eosinophils in the sputum.1
Every respiratory clinician knows the value of sputum analysis in many disease states. And to that end, inducing sputum production has been a standard in noncritical care areas. The typical regimen of hypertonic saline carried into the airway by particles from an ultrasonic nebulizer has a sound theoretical basis, but in practice getting a good sample of sputum is difficult at best.
Susan Janson, DNSc, FAAN, University of California San Francisco, uses induced sputum samples to look for the presence of changes in eosinophils as a marker of airway inflammation. She reports good correlation with pulmonary function testing in poorly controlled patients.
“We use hypertonic saline and pretreat the patient with a bronchodilator prior to the procedure,” Dr. Janson said. “Huff coughing seems to be most effective in producing the sample. We then spin down the sputum and look for the presence of squamous cells to be sure the sample is from the lower airway. We look specifically at the supernatant for specific mediators of mast cell degranulation.”
Again, it’s a matter of understanding the biochemistry of the inflammatory process that’s underlying asthma. Specific allergens (pollen, exercise, cold air) produce proteins known as IgE antibodies, which are released into the bloodstream. IgE antibodies then attach to mast cells, and further exposure to the allergen causes “cross linking” in which the allergen attaches to the mast cell via the IgE “bridge.” The mast cells then degranulate, and the stage is set for further inflammation.
Removing circulating IgE antibodies is the job of anti-IgE antibody drugs such as omalizumab (Xolair®, Genentech), which is given by subcutaneous injection. “Our target is zero eosinophils for patients with high IgE-mediated asthma with persistent eosinophils in the sputum,” Dr. Janson said.
EXHALED NITRIC OXIDE
Those familiar with the neonatal arena know the vasoactive properties of nitric oxide (NO). Inhaled NO can produce dramatic improvement in a baby’s clinical condition. For some, it’s lifesaving.
Endogenous NO is produced in three forms in the body, all derived from the amino acid L-arginine. One of these forms, inducible NO synthase (iNOS), is derived from the chemical mediators (cytokines and endotoxin) found in the asthma inflammatory cascade. It’s also known that administering glucosteroids, used to interrupt the inflammatory process, can reduce iNOS and exhaled NO (ENO).
“There is a large, runaway production of ENO in inflammation, causing too much dilation of the blood vessel and a leakage of fluid into the airway,” said Niranjan Kissoon, MD, chief of the division of pediatric critical care medicine, University of Florida Health Science Center, Jacksonville.
Therefore, measurement of ENO could be a view to the inflammatory process of asthma. Studies have shown significant correlations with ENO and bronchial responsiveness in children and a predictive value of 80 percent to 90 percent in identifying the loss of asthma control.2,3
These data were recently corroborated when researchers from New Zealand compared the sensitivity of ENO, induced sputum and conventional testing to predict which patients with known asthma had airway inflammation.
ENO was predictive in 88 percent of patients, compared to 0 percent to 47 percent for conventional spirometry and peak flow measurements. Interestingly, these same authors found the diagnostic sensitivity for induced sputum analysis (i.e., measuring sputum eosinophils) to be 86 percent compared to conventional testing.
The authors concluded that both ENO and induced sputum offer advantages compared to conventional testing for airway inflammation, but ENO is superior due its technical simplicity compared to the induced sputum.4
“The use of ENO is especially important because there are no good measures of inflammation of the lung,” Dr. Kissoon said. “We bring patients into the emergency department and treat them with bronchodilators and steroids, but that is tantamount to treating a patient with hypertension without measuring the blood pressure.”
The technology of measuring ENO involves the use of a chemiluminescence analyzer in which ENO reacts with ozone to produce a compound that can be detected with spectral analysis. This technology can directly sample exhaled gas from the patient or can store exhaled gas in a balloon for analysis at a later time. Studies suggest that a cutoff value of 16 parts per billion is an accurate method of diagnosing asthma in adults.5
Dr. Kissoon uses the technology with children as young as 6 years of age. The patient exhales for three to five seconds while the ENO reaches a plateau during the breath. Three samples are taken for reproducibility. The complexity of the test parallels a routine PFT.
Development of handheld devices for ENO is possible in the near future, Dr. Kissoon said. Imagine a day in which the patient maintains a diary of asthma symptoms and performs ENO analysis in addition to a peak flow. Now imagine the patient titrating bronchodilators and steroids in response to those measurements.
“We give bronchodilators to treat asthma,” Dr. Kissoon said, “but the treatment is cosmetic; we need to fix the underlying fact of inflammation. Medications that treat inflammation should reduce the ENO. Individuals will be able to follow their disease and adjust their medications in response to the degree of inflammation.”
Bakow is the manager of respiratory care and pulmonary diagnostics at the Penn State Milton S. Hershey Medical Center, Hershey, Pa. He’s a frequent contributor to ADVANCE.
For a list of references, please call Sharlene George at (610) 278-1400, ext. 1324, or visit www.Respiratory-care-sleep-medicine.advanceweb.com.