AIRWAY PH PLAYS UNSUSPECTED ROLE
IN ASTHMA PHYSIOLOGY

CHARLOTTESVILLE, VA-- The finding was serendipitous: While conducting controlled experiments to ensure that assays of compounds would not be artifactually influenced by a subtle variation in pH between asthmatic and nonasthmatic patients, researchers at the University of Virginia in Charlottesville found pH to be substantially lower than normal in the patients with asthma.

"We were really surprised to see that asthmatic pH was so low," said Benjamin M. Gaston, MD. In looking at compounds such as hydrogen peroxide, nitrite, and nitrate, the activities of which are known to be "fairly dramatically affected" by pH, the researchers found that pH was low in all of the patients with asthma they examined. "At that point, we could think of a lot of reasons why the pH might be low in asthma," said Dr. Gaston, who is an associate professor of pediatrics and pediatric pulmonary medicine. This led the researchers to design a prospective study to determine actual pH values during asthma exacerbations.[1]

The study included 22 patients with acute asthma, 16 of whom were treated with glucocorticoids for less than 48 hours; 19 control subjects with acute, nonrespiratory diseases; and 12 patients with stable asthma. Patients who smoked, showed clinical evidence of pneumonia, or had a chronic disease other than asthma were excluded. Asthma was defined as a history of three or more episodes of airway obstruction reversible with ß 2-agonists.

One millimeter of exhaled airway vapor condensate was obtained during 10 minutes of quiet tidal breathing through inert one-way valves and a 0.3-µm particle filter into an aluminum condensing conduit surrounded by coolant.

CONDENSATE pH IS MARKEDLY LOWER IN ACUTE ASTHMA PATIENTS

The researchers compared the mean pH of exhaled airway vapor condensate samples from each group. Subjects with early acute asthma had a mean pH of 5.23, compared with a mean of 7.65 for the control group; this difference was highly statistically significant. Those with stable asthma had a mean pH of 7.8. When patients with acute asthma were followed longitudinally during systemic corticosteroid therapy, steady increases were seen in condensate pH to normal values.

The study confirmed that airway vapor condensate from patients with acute asthma had a pH that was considerably lower than normal. "Airway acidity appears to be relevant to asthma in that it both accelerates human eosinophil necrosis and causes the conversion of endogenous nitrite to nitric oxide, " the investigators reported.

Gaston et al also extensively considered nonpulmonary causes for airway vapor acidification. For example, they closely examined three subjects who underwent bronchoscopy; in all cases, the pH of the airway vapor condensate was identical to that of the undiluted tracheal secretions but did not match the pH of salivary samples.

The investigators also used jet nebulizers to administer first albuterol, and later unbuffered solutions with a pH of 3.5, to three other patients. In no case did these treatments alter condensate pH. Previous studies of asthmatic patients have shown that ß 2-agonist therapy and methacholine challenge do not change condensate pH, and that patients without asthma who have chronic obstructive pulmonary disease, cystic fibrosis, or obstructed immotile cilia syndrome all consistently have condensate pH values above 7.0.

Taken together, the evidence suggests that abnormalities in condensate chemistry reflect intrinsic abnormalities of the airway lining fluid and that "there may be a causal relationship between airway acidification and the airflow limitation observed in acute asthma," the investigators wrote. It also suggests that "mild airway acidification may be a subtle and titratable innate host defense mechanism … to defend the airway against airborne pathogens."

AN EARLY MARKER OF INFLAMMATION?

Before this study, Dr. Gaston explained, there was no reason to presume that the airway would acidify itself. "It's a new way of looking at asthmatic airway inflammation," he added. However, it is not yet known whether airway pH is also low in patients with mild to moderate asthma. Preliminary data from a small number of such patients suggest that pH is relatively normal in this group. Thus, Dr. Gaston hypothesized, a fall in pH may be one of the first responses when an acute exacerbation occurs.

Knowing whether this does, indeed, happen would be useful as "an early warning mechanism that tells patients they are going to need to increase, at least temporarily, their anti-inflammatory medicine," he said. "I do think pH is going to be important, at some point, [as] a marker of airway inflammation--as opposed to peak flow measurements, which are very poor markers of airflow obstruction," Dr. Gaston added. "They are very crude but they are inexpensive. It would be nice to be able to use expired nitric oxide, pH, or some other condensate measurement as a specific marker of airway inflammation."

Thus far, all of the study subjects with asthma who had an exacerbation also demonstrated a fall in pH. "We also find prospectively that when people with asthma start to get a rhinovirus infection, their pH starts to fall; it's a very good marker for whether or not they have asthma. It doesn't seem to be that there's a subpopulation in whom the pH falls," according to Dr. Gaston. He admitted, however, that the number of patients who have been studied to date is limited.

LOOKING TO THE FUTURE

In addition to studying larger groups of patients, the next steps are to find out why the pH is so low, to examine patients who have severe asthma exacerbations, and to validate these findings using direct measurements. "Fortunately, very few patients with asthma have respiratory failure, but when that happens, we need to look at the airway pH and see if it matches these condensate pHs," Dr. Gaston said.

If airway acidification is proven to have a causative role in asthma exacerbations, its clinical utility is currently limited. As Dr. Gaston noted, no treatment for low airway pH is available at present. However, researchers will have the opportunity to study currently available asthma medications to determine which are best at preventing a fall in pH. And new therapies could be developed. He added that it will be interesting to find out whether leukotriene receptor antagonists or inhaled corticosteroids are better at preventing a fall in pH.

Dr. Gaston also cautioned that these findings are preliminary. "At this point, I don't want people to go down in their basements and nebulize baking soda. There are a lot of interesting aspects as to why pH is low and we're still sorting that out. When we figure out exactly why the pH is low, it will help us to be able to recommend specific therapies."

--Debra Hughes

Reference
1. Hunt JF, Fang K, Malik R, et al. Endogenous airway acidification. Implications for asthma pathophysiology. Am J Respir Crit Care Med. 2000;161:694-699.