COMMENTARY

Three Common Comorbidities With Asthma: Does Their Treatment Improve Outcomes?

Sidney S. Braman, MD, Master FCCP; Linda Rogers, MD, FCCP

Disclosures

August 13, 2018

Editorial Collaboration

Medscape &

Sidney S. Braman, MD, Master FCCP: Hello. My name is Dr Sidney Braman. I am a professor of medicine at the Icahn School of Medicine at Mount Sinai and the director of the Pulmonary Disease Management Program at Mount Sinai Hospital in New York City. Today I am joined by my colleague, Dr Linda Rogers. Prof Rogers is the clinical director of the Asthma Program at the Mount Sinai National Jewish Health Respiratory Institute in New York City. We are speaking to you as part of a collaboration between Medscape and CHEST.

The comorbidities of asthma have become recognized more and more in the past several years. In 2016, a meta-analysis of 11 studies comprising nearly half a million patients with asthma showed a strong association between asthma and cardiovascular disease, as well as systemic hypertension and gastrointestinal (GI) diseases.[1] These findings were also demonstrated in the National Health and Nutrition Examination Survey (NHANES), which found that nearly half of adult patients with asthma had at least one medical comorbidity that was associated with poor asthma outcomes.[2] For example, patients with asthma and depression have an 11-fold increase in the likelihood of an asthma exacerbation. Patients who have gastrointestinal reflux disease (GERD) have a fivefold increase in exacerbation, and patients with obstructive sleep apnea have a fourfold increase in exacerbation.

We know that asthma is a common disease, one that affects perhaps 8% of the American population.[3] There are other common diseases that might occur incidentally [in patients with asthma]. Hypertension, for example, can be seen in more than [50% of Americans in the general population]. [Editor's note: The author misspoke; the correct percentage is 50%, not 30%.] Therefore, the presence of both asthma and hypertension in a patient may be coincidental.

There are, however, other comorbidities that are part of the pathogenesis of, or possibly the cause of, asthma. Dr Rogers and I would like to discuss three of these comorbidities: GERD, rhinitis (both allergic and nonallergic), and obstructive sleep apnea.

GERD

Braman: I am going to ask Dr Rogers to begin by discussing the relationship between GERD and asthma.

Linda, I think there are two aspects of our discussion. The first relates to the association of asthma with the comorbidity, and the second relates to whether treating the comorbidity affects asthma outcomes.

Linda Rogers, MD, FCCP: You ask two very important questions: What is the relationship between reflux and asthma, and does treatment of reflux, particularly with proton pump inhibitors (PPIs), improve asthma outcomes? Both of these questions are difficult to answer.

We know that the prevalence of reflux and asthma is quite high. If you take the gold-standard test, which is the [24-hour] pH probe study, 40%-60% of patients with asthma will be found to have GERD.[4] The prevalence of GERD in patients with asthma is higher than that of the general population, and there are two mechanisms that may explain the relationship between asthma and GERD.

The reflux may be exacerbating the patient's asthma, and one mechanism by which that may take place is something called the reflux theory, wherein direct aspiration of GI contents into the airway triggers inflammation and bronchoconstriction.[5] However, because innervation of the GI tract and the airways is common embryologically, there can be reflux-related effects. For example, acid can contribute to bronchoconstriction even when it is instilled into the upper airway but does not enter the lower airway.

[M]any of the medications we use to treat asthma...may impact the likelihood of developing reflux.

These are two mechanisms by which [asthma and GERD] may be related. It is also possible that other mechanisms associated with asthma increase the likelihood of reflux. One mechanism occurs in the setting of severe asthma in which swings in intrathoracic pressure may alter the pressures dynamic across the lower esophageal sphincter, promoting reflux. In addition, many of the medications we use to treat asthma, such as beta-agonists and theophylline, may impact the likelihood of developing reflux due to their effects on the lower esophageal sphincter.

To get back to your main question of whether treating reflux-associated conditions with medicines, such as PPIs, improve asthma outcomes, data are very limited, with two general study categories. The first category comprises studies in which investigators treated patients who had both asthma and symptomatic reflux. Though findings from these studies[6,7,8] demonstrated some modest effects of PPI treatment on some asthma outcomes, the effects were not particularly dramatic. Conversely, a study conducted by our group, the American Lung Association (ALA) Asthma Clinical Research Centers (ACRC) network, followed (1) patients who had modest histories of reflux (patients who experienced reflux symptoms twice a week or less) and nocturnal asthma symptoms, and (2) patients who had uncontrolled asthma, and found that PPIs did not have any beneficial effects on asthma.[4,9,10,11]

How do you put this all together? I think that there are very limited data showing PPIs to have a positive impact on asthma. I do not think this precludes a relationship between reflux and asthma, particularly symptomatic reflux and asthma and laryngopharyngeal reflux and asthma. These issues have not been well addressed by the current literature.

In my practice, I recommend a combination of diet and lifestyle modification, which I emphasize heavily, along with judicious use of PPIs. I prescribe PPIs to patients only when they have straightforward indications based on GERD symptoms.

Allergic and Nonallergic Rhinitis

Braman: The story that you have just told us about GERD is akin to that of rhinitis, chronic allergic rhinitis, nonallergic rhinitis, sinusitis, and asthma. There is probably an even stronger association between asthma and rhinitis. About 80%-90% of patients with asthma have some form of rhinitis or rhinosinusitis, and approximately 40% of patients with chronic rhinitis have asthma.[12]

If you place an allergen in a patient's nasal passages, you can actually show an increase of asthma mediators in the lower airways and the bronchial tubes.

There is actually some very interesting experimental evidence that links the two [asthma and rhinitis]. If you place an allergen in a patient's nasal passages, you can actually show an increase of asthma mediators in the lower airways and the bronchial tubes.[13] Similarly, if you allergically challenge a lower airway in the bronchi, you can find the same mediators in the nasal mucosa.[14] There are also neural influences that affect asthma. For example, if you stimulate the nasal mucosa, you can actually see an increase in cholinergic mediators and bronchoconstriction. This reflex, the rhinobronchial reflex, was described 100 years ago, around 1918.

Rogers: Wow, that is fascinating.

Braman: So, there is an association [between asthma and rhinitis]. There are also a number of clinical reports indicating that treating rhinitis improves asthma. Although this has been a long-held concept, these findings were based on clinical studies that were not prospectively, randomly assigned. There was one outstanding study on this, conducted by the ALA Asthma Research Program.

Rogers: Yes, the Study of Asthma and Nasal Steroids (STAN) study.[15]

Braman: The STAN study investigated whether treating adult and pediatric rhinitis patients with an inhaled corticosteroid (mometasone) improves asthma outcomes. In the interest of time, let me just say that the findings were not positive; unfortunately, most of the important asthma outcomes were not improved.[15]

Just like with the GERD story, rhinitis treatment improves patients' rhinitis symptoms, and treating GI reflux reduces reflux symptoms.

Rogers: Yes.

Braman: As to whether treating rhinitis has a significant impact on asthma, I think the impact probably is not as significant as we would hope.

Rogers: Yes.

Rogers: The more nuanced way to look at this is that asthma symptoms are often fairly nonspecific—for example, cough, chest tightness, and shortness of breath. Many of these symptoms are also associated with comorbidities, such as chest discomfort from reflux or cough and postnasal drip from rhinitis. Sometimes it is difficult to discern [the etiology of the patient's symptom]. If treating the comorbidity improves the patient's symptom, whether that symptom is related to asthma or rhinitis, the key goal is to make the patient feel better.

Obstructive Sleep Apnea

Braman: What can you tell us about [the association between asthma and] sleep apnea?

Rogers: As we discuss these three comorbidities, you can see increasing parallels that exist among them. There is almost a bidirectional relationship between asthma and rhinitis and between asthma and GERD. Likewise, sleep apnea is very common in patients with asthma.

As demonstrated in mechanistic studies, the effects of asthma on the upper airway can trigger bronchoconstriction. Similarly, some of the resulting swings in pressure from asthma can cause upper airway collapse and trigger sleep apnea.

I keep going back to the ACRC network because a real interest of our group has been looking at the comorbidities associated with asthma. We tried to look at issues surrounding sleep apnea and asthma because a few small studies demonstrated that treating sleep apnea with continuous positive airway pressure (CPAP) reduced bronchial-type reactivity—as demonstrated by the methacholine challenge. As a group, we were very interested in seeing if CPAP would actually improve asthma in patients who did not have sleep apnea. Our study, the CPAP study, looked at a sham-CPAP with no pressure (just humidified air) and two levels of pressure in patients with asthma who did not actually have sleep apnea. The results of the study demonstrated improvements in asthma across all three groups.[16]

We were not able to specifically demonstrate the benefit of the actual CPAP levels; though there were no differences in study logs, all of the patients in the study improved. It is possible that humidified air alone may reduce bronchial hyperreactivity, but we were unable to resolve whether CPAP improves asthma.

Similarly, if a patient wakes up at night choking, is it due to his or her asthma or sleep apnea? It is hard to tease out [the cause of symptoms] at times, and often, if the patient is tested for sleep apnea and has indications for treatment, we should treat him or her based on sleep apnea alone. Whether CPAP improves asthma outcomes is a question that will need more research going forward.

Braman: We hope we have provided some insights about these three common comorbidities with asthma.

This is Dr Sidney Braman with Dr Linda Rogers. On behalf of the collaboration between Medscape and CHEST, we thank you for listening.

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