Exercise induced bronchoconstriction in adults: evidence based diagnosis and management

While we appreciate the work regarding Vitamin C as an intervention to aid in the management of EIB, the nature of the Clinical Review does not allow for a comprehensive systematic review of the literature to be presented. The format of this article is 1800-2000 words and is meant to provide non-specialists an overview for the diagnosis and management of the condition of interest. As such, management is only one part of our article, and we included only the information which we deemed was most impactful by current available evidence. 1 The pharmaceutical intervention section only accounts for about 10% of our text.

Hemilä states that “EBM requires that the literature searches should be thorough, and RCTs and systematic reviews should be the primary focus of the searches” and implies that the literature search was not sufficient because the Vitamin C literature was not included in this review. After performing our literature search, it was clear that the wealth of the evidence on management of EIB is rooted in prescription-based medications and the evidence for Vitamin C is relatively limited. Hemilä’s 2013 systematic review and meta-analysis of Vitamin C on EIB includes a total of 40 patients across three studies. 2 Hemilä’s 2014 review is limited to the same exact three studies. 3 This small sample demonstrating efficacy of Vitamin C pales in comparison to studies examining beta-agonists, LTRAs, and inhaled corticosteroids – the three pharmaceutical interventions mentioned in our text. Perhaps there is funding bias which allows more studies to be done on prescription therapies compared to vitamins, but the end result is that considerably more evidence is available for drugs such as beta-agonists than natural remedies in the management of EIB.

Ironically, Cohen’s 1997 study, 4 which accounts for half of the subjects in Hemilä’s reviews, appears to have some reporting bias in the results and actually concludes the “efficacy of Vitamin C in preventing EIA cannot be predicted.” The authors provided Vitamin C and placebo in a randomized, placebo-controlled crossover trial to 20 individuals (ages 7 through 28 years), and reported that 9 individuals had a positive response to Vitamin C, and another 2 individual having some level of protective effect. Thus, the remaining 9 individuals (45% of their subject pool) did not have a favorable response to Vitamin C. This is not to say that Vitamin C is not effective, but rather suggests that nearly half of the population tested may be non-responsive to it. Regardless, our Clinical Review focused on adults, whereas Cohen’s study focused on the pediatric population and would not be appropriate to include, which would leave only 20 adult subjects of data to use as evidence.

Indeed, Parsons does mention the potential benefit of Vitamin C supplementation for EIB, and considered it to have “weak evidence,” along with other dietary / nutritional interventions, such as a low sodium diet, fish oil, and lycopene. There simply is not sufficient space to include all of these non-prescription-based interventions with weak evidence in our Clinical Review. However, we did include warm-up as a non-prescription based recommendation in the text, as it had stronger evidence (systematic review which included 7 studies with 128 participants).

Hemilä states that our omitting the evidence regarding Vitamin C may be explained by “bias in mainstream medicine against treatments that do not need prescriptions.” While this indeed may be the case with some authors, Hemilä should be aware that the first / senior author (JMS) has published extensively on the health benefits red wine antioxidant resveratrol, including a systematic-review and meta-analysis demonstrating that this over-the-counter nutritional supplement is beneficial in the management of diabetes mellitus,5 and a clinical trial demonstrating its potential utility in preventing atherosclerosis, 6 as well as studies on other natural products (e.g., ginger supplementation 7). As such, it is not appropriate to imply that the authors are biased against natural treatments and “dismissed” evidence for Vitamin C.

Evidence based medicine is centered on using current best evidence for making decisions regarding patient care, and these decisions must consider the quantity and quality of available evidence. It is possible that Vitamin C is one of many potential intervention strategies that could be further explored in clinical research on the management of EIB. However, at present, we feel there is not a sufficient number of high quality studies with large sample sizes to warrant the inclusion of Vitamin C (and various other non-prescription and prescription interventions) in a concise review on EIB.

References

1. Smoliga JM, Weiss P, Rundell KW. Exercise induced bronchoconstriction in adults: evidence based diagnosis and management. BMJ 2016;352:h6951.
2. Hemila H. Vitamin C may alleviate exercise-induced bronchoconstriction: a meta-analysis. BMJ open 2013;3(6).
3. Hemila H. The effect of vitamin C on bronchoconstriction and respiratory symptoms caused by exercise: a review and statistical analysis. Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology 2014;10(1):58.
4. Cohen HA, Neuman I, Nahum H. Blocking effect of vitamin C in exercise-induced asthma. Archives of pediatrics & adolescent medicine 1997;151(4):367-70.
5. Hausenblas HA, Schoulda JA, Smoliga JM. Resveratrol treatment as an adjunct to pharmacological management in type 2 diabetes mellitus--systematic review and meta-analysis. Molecular nutrition & food research 2015;59(1):147-59.
6. Agarwal B, Campen MJ, Channell MM, et al. Resveratrol for primary prevention of atherosclerosis: clinical trial evidence for improved gene expression in vascular endothelium. International journal of cardiology 2013;166(1):246-8.
7. Matsumura MD, Zavorsky GS, Smoliga JM. The Effects of Pre-Exercise Ginger Supplementation on Muscle Damage and Delayed Onset Muscle Soreness. Phytotherapy research : PTR 2015;29(6):887-93.