Comparison of Inhaled Corticosteroids, Mast Cell Stabilizing Agents, and Leukotriene Receptor Antagonists in the Treatment of Exercise-Induced Bronchoconstriction
By Matthew Kuik, Tom Schneider, and Bryan Jackler
While many individuals suffer from asthma in their everyday lives, a significant number are misdiagnosed with this condition rather than the true source, exercise-induced bronchoconstriction (EIB). Of the pharmacological methods used to treat EIB, none are specifically intended to protect those who suffer from the condition, but are instead identical to treatments prescribed to asthma patients. This meta-analysis was designed to compare these treatments and investigate which pharmacological method best manages the symptoms of EIB: inhaled corticosteroids, leukotriene receptor antagonists, or mast cell stabilizing agents. This will allow those diagnosed with the condition to make a more informed treatment decision. We found that the mean percent fall from baseline in percent Forced Expiratory Volume (%FEV) values for inhaled corticosteroids, leukotriene receptor antagonists, and mast cell stabilizing agents were improved by 10.205%, 6.544%, and 25.850%, respectively (SD = 4.618, 4.218, 8.651; p < 0.0001) compared to the placebo. Based on the studies analyzed, mast cell stabilizing agents were determined to be the most effective treatment for EIB. This may be due to the drug’s direct impact on the mast cells, which cause inflammation through the release of histamine. With mast cell stabilizing agents, those with EIB may be better able to control the symptoms of the condition, exercise for longer periods of time, and have improved lung function following strenuous activity. Our findings suggest that those who are diagnosed with EIB should consider using mast cell stabilizing agents as a method to best manage their symptoms following exercise.
Exercise-induced bronchoconstriction (EIB) is a distinct form of airway hyperresponsiveness, in which the airways narrow significantly and forcefully after bouts of strenuous exercise due to a range of bronchoconstrictor stimuli . The severity of EIB is largely dependent upon the individual, the type of activity, and the environmental conditions in which the exercise is done. While common symptoms of EIB include coughing, wheezing, chest tightness, dyspnea, and fatigue, the extent of the symptoms can range from minor impairment in performance to severe bronchospasm and respiratory failure, although the latter is much less prevalent . A bronchospasm is an acute, transient constriction of the muscles lining the bronchioles. There are three separate phases that EIB occurs in: severe bronchospasm, the refractory period, and minor bronchospasm.
Because airway hyperresponsiveness is a key indicator of asthma, EIB is reported frequently in asthmatic patients. However, recent research has found that EIB is also prevalent in the absence of chronic asthma in populations of athletes and children . It is estimated that EIB occurs in up to 90% of asthmatic patients; it also has an incidence of greater than 10% of the nominally non-asthmatic general population . Another difference between asthma and EIB is the presence of mast cell activation following exercise. Mast cells are a type of white blood cell that release inflammatory histamines in response to certain stimuli. In patients with asthma, there is a distinct absence of mast cell activated inflammation, where no increase is observed in histamine or white blood cell count measured from bronchoalveolar lavage following exercise tests, while activation and inflammation are present for those with EIB . Another key difference between the conditions is their effect on resting lung capacity. Those with chronic, uncontrolled asthma will normally wheeze while at rest and have abnormal peak airflow, whereas those with EIB have normal lung function and peak airflow at rest. Asthma is typically treated through long-term therapy with additional medications before or during exercise. By contrast, EIB can be treated with medication exclusively before periods of exercise, as symptoms only occur at a specific level of exertion .
The mechanism of EIB is not completely understood, and may be multifactorial; the main mechanisms that have been distinguished are airway cooling due to the intake of dry air and thermal reheating of the airways post-exercise. Reheating increases hydrostatic pressure in the capillaries, leading to a swelling of the airways. Similarly, breathing in dry air causes osmotic and thermal changes resulting in water loss from the airway surface. Receptors respond to this stimulus by producing excess mucus to rewet the pathways. The dryness also provokes coughing to remove material that is not being swept up by cilia in the bronchial tubes . Airway exposure to environmental pollutants like chlorine in swimming pools can also place individuals at a higher risk for developing EIB. It is believed that environmental conditions such as these may act as allergic “triggers,” leading to bronchospasms by promoting inflammatory responses .
The pharmacotherapeutic agents used to prevent EIB are typically the same treatments used to control the mechanisms that induce asthma, even though it is known that they may not coincide. This leads to varying degrees of effectiveness when treating the symptoms of EIB alone . There are currently many recommendations for treating EIB, the three most prominent being inhaled corticosteroids (ICS), leukotriene receptor antagonists (LTRA), and mast cell stabilizing agents (MCSA).
It has been shown that inhaled corticosteroids (ICS) not only control the symptoms of EIB, but also improve pulmonary function. Corticosteroids are a part of the larger class of steroids called glucocorticoids, which bind to glucocorticoid receptors in a cell to regulate gene expression, including the repression of cytokines that cause inflammation . Different ICSs will vary in their therapeutic and adverse effects depending upon the individual using the medicine because the mechanism for targeting only genes that produce therapeutic effects has yet to be found . While ICSs have been used as an effective, long-term method of managing the symptoms of both asthma and EIB, there are many adverse effects that can occur if the corticosteroid begins to bind a receptor that affects an incorrect gene. These adverse effects include glaucoma, cataracts, reduced growth in children, osteoporosis in the elderly, and adrenal suppression . The objective in prescribing ICS for a therapy treatment is to use the lowest dose possible, while also limiting the risk of treatment failure, which can vary individually.
Leukotriene receptor antagonists (LTRAs), also called leukotriene modifiers, reduce the effects of EIB and protect airways from bronchospasms by blocking the actions of leukotrienes, making exposure and inhalation of various pollutants less likely to cause a bronchospasm. Leukotrienes are a class of inflammatory chemicals that are released from the body when contact with an allergen occurs . In this analysis, the focus will be on Montelukast, the most commonly used LTRA. Leukotriene modifiers like Montelukast have shown no tolerance formation or exacerbation of rebound impaired of lung function after use of the drug has ceased . However, there are side effects when taking Montelukast, ranging from psychological changes such as mood disorders and hallucinations to increased risk of upper respiratory infections and coughing .
The third pharmacological method in treating EIB is use of mast cell stabilizing agents (MCSA). One example is cromolyn sodium, which prevents mast cells from releasing cytokines, small proteins that attract histamines, causing the vasodilation and inflammation seen in EIB . Cromolyn sodium is one of the most commonly used mast cell stabilizers for treating EIB; however, the exact mechanism that makes it effective at decreasing the symptoms of EIB is unknown . Cromolyn sodium is fast-acting and can result in an inhibition in decrease of %FEV, a metric that reflects the degree of ease of a person’s breathing, as quickly as just one minute after initial treatment . Inhaling cromolyn sodium has not shown any long-lasting negative side effects, but some milder side effects include a bad taste in the mouth, coughing, nausea, and throat irritation and dryness .
The purpose of this meta-analysis is to analyze and compare the effectiveness of ICS, LTRAs, and MCSA treatments on controlling the symptoms of EIB. This was assessed by analyzing studies that examined the effects of these drugs on the change in %FEV over the course of one minute in individuals diagnosed with EIB. FEV has become a popular method for analyzing pulmonary function as it offers a simple, noninvasive approach to objectively measure lung capability. The lower the %FEV fall value, the better the lungs are functioning due to reduced airway obstruction .
While it is generally understood that ICSs are recommended as the initial therapy to treat the symptoms of asthma and EIB in newly diagnosed patients, we believe that leukotriene modifiers will have a greater impact on managing the effects of EIB. This is because leukotriene modifiers act directly on G-protein coupled receptors which cause inflammation, allowing a preventative control of EIB instead of reducing the effects after an attack has occurred . The mechanisms of an ICS treatment are meant to treat widespread inflammation through the repression of a multitude of genes in cells throughout the body, whereas LTRAs target specific receptors in the body to reduce mast cell response [5, 12]. Identifying the most effective pharmacological treatment method for EIB will enable patients to make a more informed decision about their treatment regiment.
Literary search: In order to identify studies that reported the effects of ICS, LTRA, and MCSA on the forced expiratory volume of individuals diagnosed with EIB, we utilized the electronic databases of PubMed and Web of Science. To generate a list of studies, we used keywords such as “inhaled corticosteroids,” “leukotriene receptor antagonists,” “mast cell stabilizing agents,” “exercise-induced bronchoconstriction,” “EIB,” and “FEV.” We also included articles found through searches in the citations of both review articles and studies that held relevant information and met the criteria as explained in the following Study Selection section.
Study Selection: Of the studies found, we included only those that met the following criteria: studies of at least 15 subjects; the subjects had a minimum fall in %FEV of 10% after exercise; a standard exercise test was completed in the lab; reported dosage used in each trial; and reported both baseline and post-treatment mean FEV test results reported as “maximum fall in %FEV.” Studies were excluded if the dose of the drug being tested had been paired with another medicinal method or if more than 50% of the original subjects had dropped out of the study due to exacerbated asthma symptoms. Studies that utilized bias-reducing methodologies such as the double-dummy technique, where the placebo and treatment are administered blindly in alternating trials, were considered more relevant to our meta-analysis.
Statistical Analysis: For each of our individual treatments, we found the mean %FEV fall compared to mean baseline and placebo falls. Taking these values, we used a single-factor Analysis of Variance (ANOVA) test to find any statistically significant differences between the treatment types. We used an alpha level of 0.05 to determine statistical significance of the data. While the ANOVA test gave us a total comparative p-value for all three treatment types, a Tukey test was also completed to compare the data of two treatment types at a time in order to find if there were any significant differences between them.
Inhaled Corticosteroids (ICS): When analyzing all ten studies focusing on ICS as the therapeutic treatment for EIB, there were a total of 493 participants, with an age range from 6 to 45 years old. The average length of the studies was 10.6 weeks. Nine of the ten used a double-blind procedure for the study. The mean fall in %FEV for all placebo trial groups was 21.68% (SD 6.69), while the mean fall in %FEV for treatment groups using ICS was 9.81% (SD 5.53). An ANOVA test produced a p-value of 0.0001, showing that there is a statistically significant difference between the % fall in FEV in the placebo-controlled group and in the ICS trial group, as seen in Figure 1.
Leukotriene Receptor Antagonist (LTRA): Of the six studies focusing on the LTRA drug Montelukast, five utilized double-blind, randomized cross-over studies, and one used a double-blind non-crossover study. 252 people with ages ranging from 4 to 65 participated in the trials. Tests ranged from under 24 hours to over 8 weeks of treatment. The mean %FEV falls for placebo and LTRA Montelukast treatment groups were 22.66% (SD 8.18) and 16.39% (SD 6.92), respectively. Using ANOVA, a significant difference between the placebo and treatment groups was found, with a p-value of 0.0390 (Figure 2).
Mast Cell Stabilizing Agents (MCSA): From the six placebo-tested studies that sought to quantify the effects of the mast cell stabilizing agent cromolyn sodium, three studies were conducted in a double-blind fashion and three were single-blind. Across these studies, the 99 total subjects ranged from ages 7 to 49 years old. Studies were as brief as one day and as lengthy as six weeks. Inhaling saline or substances that tasted similar to the MCSA were used as placebos in all studies. The mean fall in %FEV for the placebo group was 44.08% (SD 6.86%), while the mean fall in %FEV for the cromolyn sodium MCSA group was 18.21% (SD 5.34%) (Figure 3). An ANOVA test was run comparing fall in %FEV of the placebo to fall in %FEV after inhaling MCSA, and the p-value of this data set was 0.0013, showing significance.
Comparison: Our results have found that all three treatment types are effective in limiting the symptoms of EIB, but with varying degrees of effectiveness. The difference between placebo and treatment fall in %FEV was calculated for ICS (10.205%; SD 4.618), LTRA (6.544%; SD 4.218), and MCSA (25.850%; SD 8.651). The ANOVA run produced a p-value of <0.0001, showing that all three medicinal treatments reduced the effects of EIB by decreasing %FEV fall from baseline compared to placebo treatments (Figure 4). A Tukey test was then used to determine significance between these three treatment groups by comparing each drug’s reduction in % fall in FEV in three separate ways; ICS:LTRA, ICS:MCSA, and LTRA:MCSA. It was found that ICS and LTRA were not significantly different; however, the differences in % fall of FEV using MCSA treatment were significantly higher than both ICS and LTRA treatments, where both comparisons had a p-value of <0.01 (Figure 4).
Our analysis finds MCSA as a more effective treatment for EIB than either ICS or LTRA. The MCSA treatment proved to be a significantly more effective pharmacological solution for EIB symptoms. This finding may be due to the fact that mast cells are the direct cause of inflammation in the lungs. Targeting mast cells may be important through the blocking of calcium ion flow, preventing the release of the inflammatory agent histamine .
When analyzing treatments of ICS for EIB, it was found that the maximal fall in %FEV was lower in the treatment group than in the placebo group. When comparing the effectiveness of ICS therapy to the placebo, there was a statistically significant difference (p-value = 0.0001) (Figure 1). These results were as we had expected, as ICS are used widely to repress the symptoms of inflammation for patients with asthma, as well as being prescribed for individuals with EIB.
In the analysis of LTRA treatments for EIB, it was found that the mean %FEV fall was lower in the treatment group than the placebo group (Figure 2). This was expected as LTRAs, like Montelukast, are used actively in the pharmaceutical industry to treat asthma and EIB, supporting that LTRAs are a viable form of EIB reducer. Differences in the studies’ methodologies may have led to variability, such as the baseline FEV values, as differences among participants may show some importance in the responses to each treatment.
An interesting difference between the three classes of drugs was the difference in duration of the treatment. Studies on ICS tended to focus primarily on long term analysis of its effect on pulmonary inflammation. Since it is a treatment associated more with asthma than EIB, it was not studied with the sudden change in lung function associated with EIB. The MCSA and LTRA studies focused more on shorter term effects, as both are used as fast acting responders after exercise-induced airway obstruction has occurred. Even though these are all viable ways to treat EIB, as seen in the individual analyses for each treatment type, they are used in different ways.
Our findings suggest that MCSA treatment may be a better alternative than ICS and LTRA for the control of EIB symptoms. We believe that this is primarily because MCSA blocks histamine release and consequently shuts down inflammation at its root . Future studies may be able to help affirm our findings through a wider range of testing. Long term MCSA and LTRA treatment need to be further studied, as these studies are less prevalent. This testing could be useful in determining which treatment provides the most beneficial balance between cost, FEV outcome, and convenience for the patient. Additionally, a future study could attempt to negate the differences among individuals by giving each participant each treatment with proper washout periods in between trials. Age has not been studied sufficiently regarding FEV response, so it may be beneficial to study age groups in order to investigate the role of age between treatments and results. Similarly, studies on the differences between well-trained athletes and the general population are lacking, so it may be useful to compare elite athletes who compete in cold-environment sports to non-athletes who work in a low temperature setting.
Our meta-analysis of various pharmacological treatments used to control the symptoms of EIB showed that MCSA provides the greatest relief following periods of strenuous exercise because it causes the maximum fall in %FEV. Due to the drug’s direct impact on cells that cause inflammation, those with EIB may find that MCSA can control their symptoms to a greater extent than their current medication. Our findings will help enrich understanding of not only the biological mechanisms that cause EIB, but also how these three treatment options interact with those mechanisms. Continued research will hopefully lead to an effective and convenient method to prevent or minimize the symptoms of EIB, a condition affecting a large percentage of the general public.
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