3 Scott JA, North ML, Rafii M, Huang H, Pencharz P, Subbarao P, Belik J, .... 1 Jaramillo JD, Wilson C, Stinson DS, Lynch DA, Bowler RP, Lutz S, Bon JM,.
LETTERS significant correlations among airway ADMA and FENO (4). We did not measure ADMA in our study. ADMA has been associated with changes in hemodynamic parameters that associate with cardiovascular risk (5, 6). To explore a possible link between PPI treatment and hemodynamic changes in a post hoc analysis, we determined the associations among PPI treatment status, metabolizer phenotype, and key hemodynamic measures before and after the intervention period. Using our original statistical approach, we found that increasing PPI exposure was not associated with changes in blood pressure, heart rate, pulse pressure, mean arterial pressure, mid blood pressure ([sytolic blood pressure 1 diastolic blood pressure]/2), pulse pressure index, or rate pressure product (data not shown). However, we did see a weak trend between PPI exposure group and changes from baseline in systolic blood pressure (placebo 0.0 vs. lansoprazole-treated poor metabolizer 13.5; P = 0.09). It is biologically plausible for excess PPI exposure to increase susceptibility to asthmagenic pathogens and increase ADMA, leading to altered NOS activity and airway inflammation. However, further research is needed to confirm these speculations. Despite the fact that long-term use of PPIs is common, current US Food and Drug Administration recommendations for dosing is limited to short-term use (up to 12 weeks). We very much agree with Sukhovershin and colleagues that considering PPIs’ multiple known adverse effects and limited research into long-term effects, judicious use of PPIs is warranted and should be conducted with close guidance from a medical professional. Author disclosures are available with the text of this letter at www.atsjournals.org. Jason E. Lang, M.D., M.P.H. Nemours Children’s Hospital Orlando, Florida and
FEV1 Can Be Associated with Reduced Values after Vigorous Exercise in Healthy Adolescents To the Editor: I read with great interest the study “Vigorous exercise can cause abnormal pulmonary function in healthy adolescents,” recently published by Abosaida and colleagues (1). The study considered more than 50 healthy adolescents who underwent a constant and progressively increasing work rate exercise testing protocol on a cycle ergometer. The study was designed so that participants had at least 2 weeks between the test protocols to allow for complete recovery, but not more than a month, to reduce chances of participants showing a change in respiratory tests’ outcomes unrelated to the experimental design, and in accordance with the American Thoracic Society guidelines (2). The main result of the study was that 10 participants had a decrease in FEV1 after vigorous exercise testing. Of these participants, three showed a decrease only after the constant work rate test, five only following the ramp test, and two after each testing protocol. The article concludes that healthy adolescents demonstrate subtle bronchoconstriction after exercise. Letters
Nemours Children’s Clinic Jacksonville, Florida Janet T. Holbrook, Ph.D., M.P.H. Johns Hopkins Bloomberg School of Public Health Baltimore, Maryland John J. Lima, PharmD. Nemours Children’s Clinic Jacksonville, Florida for the American Lung Association-Asthma Clinical Research Centers
References 1 Lang JE, Holbrook JT, Mougey EB, Wei CY, Wise RA, Teague WG, Lima JJ; American Lung Association-Asthma Clinical Research Centers. Lansoprazole is associated with worsening asthma control in children with the CYP2C19 poor metabolizer phenotype. Ann Am Thorac Soc 2015;12:878–885. 2 Lima JJ, Lang JE, Mougey EB, Blake KB, Gong Y, Holbrook JT, Wise RA, Teague WG. Association of CYP2C19 polymorphisms and lansoprazole-associated respiratory adverse effects in children. J Pediatr 2013;163:686–691. 3 Scott JA, North ML, Rafii M, Huang H, Pencharz P, Subbarao P, Belik J, Grasemann H. Asymmetric dimethylarginine is increased in asthma. Am J Respir Crit Care Med 2011;184:779–785. 4 Carraro S, Giordano G, Piacentini G, Kantar A, Moser S, Cesca L, Berardi M, Di Gangi IM, Baraldi E. Asymmetric dimethylarginine in exhaled breath condensate and serum of children with asthma. Chest 2013;144:405–410. 5 Lewington S, Clarke R, Qizilbash N, Peto R, Collins R; Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002;360: 1903–1913. 6 Robinson TG, Dawson SL, Ahmed U, Manktelow B, Fotherby MD, Potter JF. Twenty-four hour systolic blood pressure predicts long-term mortality following acute stroke. J Hypertens 2001;19:2127–2134. Copyright © 2015 by the American Thoracic Society
I think that the effect of fatigue, and especially central command, could have been overlooked in this study. Also, this study shows association between vigorous exercise and decreased FEV1, not causality, as the title suggests. It is possible that the cause of the observed FEV1 reduction after vigorous exercise is not exercise-induced bronchoconstriction. Table 2 in the article shows that participants with abnormal FEV 1 had a (not significant) reduction in exercise capacity in terms of work rate that they could sustain for a given heart rate. No significant difference was detected in any of the other physiological variables measured; this may depend on the complex nature of the cardiac and respiratory parameters measured such as heart rate and ventilation, especially at heart rates of 80–90% peak heart rate. These results could suggest that a greater fatigue may be experienced by participants presented in the abnormal FEV 1 group, irrespective of FEV 1 itself. For example, it is possible that different baseline fitness levels, not taken into account or not detectable by the exercise testing protocols used, may be associated with the reduced exercise capacity. For example, accumulation of blood lactate could help show whether this may be the case (3). 1111
LETTERS Most important, the FEV1 test requires participants’ collaboration and volitional effort, which could be reduced after vigorous exercise (4), as is briefly mentioned in the discussion of this study (1). It is possible that central fatigue after vigorous exercise has reduced some participants’ capacity to obtain an FEV1 result comparable with the preexercise values; this effect could be entirely unrelated to exerciseinduced bronchoconstriction. Central fatigue was essentially not controlled for in this study, and it is difficult to exclude it as a factor determining reduced FEV1 after vigorous exercise in some participants. The concept that “The bronchoconstrictive effect found after exercise depends on the individual reaching near their limit of physiologic response to exercise,” and the reported observation that “the flow-volume loops before and after exercise did not reveal any limitation of the inspiratory flow in any responder” could support the alternative explanation proposed here. In conclusion, I think we need additional evidence to support the conclusion that vigorous exercise per se can cause abnormal pulmonary function in healthy adolescents. Author disclosures are available with the text of this letter at www.atsjournals.org.
Reply From the Authors: We thank Dr. Formenti for bringing to our attention his constructive points on this study. The effect of fatigue of peripheral respiratory pump muscles or central command is certainly a necessary consideration when interpreting lung function testing. As mentioned in the Discussion, using spirometry versus full forced pulmonary function maneuvers would be one way to minimize fatigue. Other methods of measuring respiratory muscle strength, such as maximum inspiratory/expiratory pressures, may be incorporated, but we elected not to, as they may magnify any postexercise abnormal finding. Central respiratory fatigue should be considered when evaluating for exercise-induced bronchospasm, which could be done via such methods as diaphragm electromyography (1), twitch occlusion, or magnetic stimulation (2). Such tests would be an excellent addition to future studies to determine the exact cause of the abnormal lung function postexercise. For this initial study, we chose not to include these more invasive diagnostic measures. However, as subtle differences in pulmonary function were noted between the results of the ramp and submaximal protocols, we agree with Dr. Formenti that further investigation into this area of exercise-induced bronchospasm would benefit from evaluations of central respiratory drive.
Erratum: Reduced Bone Density and Vertebral Fractures in Smokers. Men and COPD Patients at Increased Risk The authors would like to make a correction to their article published in the May 2015 issue of the Journal (1). The middle initial was incorrect for Mr. Stinson; his name should have appeared as Douglas S. Stinson.
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Federico Formenti, D.Phil., Ph.D., M.Sc., B.A. University of Oxford Oxford, United Kingdom
References 1 Abosaida A, Chen JJ, Nussbaum E, Leu SY, Chin T, Schwindt CD. Vigorous exercise can cause abnormal pulmonary function in healthy adolescents. Ann Am Thorac Soc 2015;12:872–877. 2 Crapo RO, Casaburi R, Coates AL, Enright PL, Hankinson JL, Irvin CG, MacIntyre NR, McKay RT, Wanger JS, Anderson SD, et al. Guidelines for methacholine and exercise challenge testing-1999: this official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. Am J Respir Crit Care Med 2000;161: 309–329. 3 Formenti F, Constantin-Teodosiu D, Emmanuel Y, Cheeseman J, Dorrington KL, Edwards LM, Humphreys SM, Lappin TR, McMullin MF, McNamara CJ, et al. Regulation of human metabolism by hypoxia-inducible factor. Proc Natl Acad Sci USA 2010;107:12722– 12727. 4 Paterson DJ. Defining the neurocircuitry of exercise hyperpnoea. J Physiol 2014;592:433–444. Copyright © 2015 by the American Thoracic Society
Author disclosures are available with the text of this letter at www.atsjournals.org. Alladdin Abosaida, M.D. Jen Jen Chen, M.D. Eliezer Nussbaum, M.D. Szu-Yun Leu, Ph.D. Terry Chin, M.D. University of California, Irvine, School of Medicine Irvine, California and Miller Children’s Hospital Long Beach, California Christina D. Schwindt, M.D. University of California, Irvine, School of Medicine Irvine, California
References 1 Lourenço RV, Miranda JM. Drive and performance of the ventilatory apparatus in chronic obstructive lung disease. N Engl J Med 1968; 279:53–59. 2 American Thoracic Society/European Respiratory Society. ATS/ERS Statement on respiratory muscle testing. Am J Respir Crit Care Med 2002;166:518–624. Copyright © 2015 by the American Thoracic Society
Reference 1 Jaramillo JD, Wilson C, Stinson DS, Lynch DA, Bowler RP, Lutz S, Bon JM, Arnold B, McDonald ML, Washko GR, et al.; COPDGene Investigators. Reduced bone density and vertebral fractures in smokers: men and COPD patients at increased risk. Ann Am Thorac Soc 2015;12:648–656. Copyright © 2015 by the American Thoracic Society
AnnalsATS Volume 12 Number 7 | July 2015
