Figures
Abstract
Background
Exertional dyspnea and exercise intolerance are frequently endorsed in Veterans of post 9/11 conflicts in Southwest Asia (SWA). Studying the dynamic behavior of ventilation during exercise may provide mechanistic insight into these symptoms. Using maximal cardiopulmonary exercise testing (CPET) to experimentally induce exertional symptoms, we aimed to identify potential physiological differences between deployed Veterans and non-deployed controls.
Materials and methods
Deployed (n = 31) and non-deployed (n = 17) participants performed a maximal effort CPET via the Bruce treadmill protocol. Indirect calorimetry and perceptual rating scales were used to measure rate of oxygen consumption (), rate of carbon dioxide production (
), respiratory frequency (f R), tidal volume (VT), minute ventilation (
), heart rate (HR), perceived exertion (RPE; 6–20 scale), and dyspnea (Borg Breathlessness Scale; 0–10 scale). A repeated measures analysis of variance (RM-ANOVA) model (2 groups: deployed vs non-deployed X 6 timepoints: 0%, 20%, 40%, 60%, 80%, and 100%
) was conducted for participants meeting valid effort criteria (deployed = 25; non-deployed = 11).
Results
Significant group (η2partial = 0.26) and interaction (η2partial = 0.10) effects were observed such that deployed Veterans exhibited reduced f R and a greater change over time relative to non-deployed controls. There was also a significant group effect for dyspnea ratings (η2partial = 0.18) showing higher values in deployed participants. Exploratory correlational analyses revealed significant associations between dyspnea ratings and fR at 80% (R2 = 0.34) and 100% (R2 = 0.17) of , but only in deployed Veterans.
Conclusion
Relative to non-deployed controls, Veterans deployed to SWA exhibited reduced fR and greater dyspnea during maximal exercise. Further, associations between these parameters occurred only in deployed Veterans. These findings support an association between SWA deployment and affected respiratory health, and also highlight the utility of CPET in the clinical evaluation of deployment-related dyspnea in Veterans.
Citation: Alexander T, Watson MA, Klein-Adams JC, Ndirangu DS, Serrador JM, Falvo MJ, et al. (2023) Deployed Veterans exhibit distinct respiratory patterns and greater dyspnea during maximal cardiopulmonary exercise: A case-control study. PLoS ONE 18(5): e0286015. https://doi.org/10.1371/journal.pone.0286015
Editor: Kalyana Chakravarthy Bairapareddy, University of Sharjah, UNITED ARAB EMIRATES
Received: August 24, 2022; Accepted: May 5, 2023; Published: May 24, 2023
This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Data Availability: All data were collected at the Department of Veterans Affairs and the signed subject consent forms and HIPAA authorizations did not include provisions for making individual data records publicly available, even in de-identified form. However, the authors can provide the “metadata” – i.e. the numerical (aggregated data) results used to generate the figures. Requests for access can be sent to: Towanda Smith, Privacy Officer, East Orange Campus of the VA New Jersey Healthcare System, 385 Tremont Ave East Orange, NJ 07018, PH: 973-676-1000 x201948, towanda.smith@va.gov.
Funding: This work was supported by Pilot Project Award # I21RX001079 from the United States (U.S.) Department of Veterans Affairs Rehabilitation Research and Development Service and supported in part by Merit Review Award # I01CX001515 and Career Development Award # IK2CX001679 from the U.S. Department of Veterans Affairs Clinical Sciences Research and Development Service. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Background
Since 2001, more than three million United States military personnel have deployed to Southwest Asia and Afghanistan (SWA) in support of multiple military operations. Over this time span a considerable increase in post-deployment respiratory symptoms has been reported, prompting concerns for the respiratory health of deployed Veterans [1–5]. The National Academies of Sciences, Engineering and Medicine concluded there is sufficient evidence of an association between SWA deployment and respiratory symptoms (i.e., cough, wheeze, and dyspnea) but insufficient evidence to support an association with respiratory conditions [6]. The non-specific nature of respiratory symptoms, particularly dyspnea on exertion, is challenging to assess as it may be present in those with and without objective pulmonary function abnormalities. Although there have been reports of a spectrum of respiratory conditions following deployment [1–5], the majority of symptomatic military personnel and Veterans remain undiagnosed after evaluation and have pulmonary function within normal limits [3,5,7,8]. For these individuals whereby dyspnea seems disproportionate to function, cardiopulmonary exercise testing (CPET) may provide unique insight though has received less attention in this population.
Dyspnea is a subjective experience of breathing discomfort that is not exclusive to the respiratory system [9]. As such, it is important to thoroughly consider all potential contributing factors (e.g., deconditioning, respiratory, cardiovascular, and/or metabolic). CPET is ideally suited for this task as it provides the opportunity to both recreate symptoms on exertion as well as identify the system(s) underlying observed limitations. Given the inhalational exposures during deployment as well as the respiratory symptoms endorsed by military personnel and Veterans, greater attention to the ventilatory responses during exercise appears warranted. Determining a mechanistic role for ventilation on exertional dyspnea is best achieved by considering both lung mechanics and the ventilatory response to metabolic stimuli [10]. Ventilatory limitation to exercise has traditionally been evaluated by comparing the minute ventilation () at the end of exercise with the predicted or measured maximal voluntary ventilation to assess breathing reserve capacity as well as
relative to the production of carbon dioxide (
) to assess ventilatory efficiency. Analyzing CPET data with attention to respiratory mechanics and efficiency might enable a greater understanding of exertional dyspnea reported following deployment.
Despite the potential benefits of using CPET to understand dyspnea and its relevance to this population of interest, few studies have thoroughly investigated exercise ventilatory responses and their relationship to dyspnea [1,3,7,11,12]. We have previously found that the components of exercise afforded insight into evaluating exercise intolerance among deployed veterans of earlier miliary conflicts [13]. Hence, the purpose of this study is to evaluate key CPET parameters and patterns in SWA deployed Veterans relative to non-deployed control participants. Our primary hypothesis was that symptomatic deployed Veterans without a diagnosed respiratory condition have inefficient ventilation patterns during maximal exercise that is associated with dyspnea. Testing this hypothesis would advance the understanding of CPET’s ability to elucidate breathing and cardiorespiratory patterns that are reflective of deployment-related dyspnea and exercise intolerance in Veterans.
Materials and methods
This observational, case-control pilot study (NCT01754922) involved two visits where participants completed questionnaires, provided blood samples, and completed physiological testing. On one of these visits, participants performed spirometry and underwent maximal cardiopulmonary exercise testing (CPET) which is the focus of the present analysis. All study procedures were conducted at the War Related Illness and Injury Study Center located within the East Orange, New Jersey Veterans Affairs Hospital. Participants were recruited from 09/01/13 to 10/01/15.
Participants
Forty-eight non-treatment seeking volunteers participated in this pilot study and were assigned to groups based on their deployment history–i.e., deployed to SWA or a non-deployed control group. The deployed group consisted of Veterans deployed to SWA (≥ 90 consecutive days) and the non-deployed control group consisted of similar era, but non-deployed, Veterans and civilians (i.e., non-exposure group). Participants from either group were excluded from the study if any of the following were present: 1) absolute contraindications to exercise testing [14], 2) pre-military history of asthma, 3) neurological impairment or disorder, 4) uncontrolled hypertension (SPB > 160 mmHg; DBP > 100 mmHg), 5) severe or moderate traumatic brain injury within the past 3 years, or 6) any contraindications for spirometry (i.e., eye, chest, or abdominal surgery in last 3 months, history of stroke, heart attack or coughing up blood in past 3 months, and history of collapsed lung or aneurysm) [9,15]. All exclusion criteria were determined via self-report and verified via electronic health record in cases where self-reported information was uncertain. Study procedures were reviewed and approved by the VA New Jersey Health Care System Institutional Review Board (IRB #01193). All participants provided written informed consent before initiating study procedures.
Questionnaires
Participants completed multiple questionnaires, including a detailed medical screening, to assess overall health and any respiratory issues. As part of the medical screening, physical activity levels (mins/day and days/week) were calculated using the short of version of the International Physical Activity Questionnaire [16]. Functional limitation questions were used to rate participant difficulty to achieve listed activities. Ratings were based on a 0–6 scale where 0 = “I don’t know”, 6 = “I don’t do this activity”, and where 1–5 ranges from “not at all difficult” to “can’t do it at all”. A rating of 3 “somewhat difficult” to 5 “can’t do it at all” was considered to be functionally limited. The Veterans version of the Short Form 36 health survey was used to examine physical (physical component summary; PCS) and mental (mental component summary; MCS) health. The normalized national average for the PCS and MCS scores is 50 with a standard deviation of 10 [17]. To measure dyspnea and other respiratory symptoms and their effect on day-to-day life, the St. George’s Respiratory Questionnaire (SGRQ) was used. In brief, this questionnaire contains four components: 1) frequency and severity of symptoms, 2) activities that cause or are limited by breathlessness, 3) an impact component on how respiratory symptoms affect day-to-day life, and 4) a total score considering all the other parts. Each section is graded from 0 to 100 with higher scores indicating greater limitations [18,19]. Self-reported environmental exposures during deployment were assessed using the US Army Public Health Command Deployment Respiratory Air Respiratory Exposures Questionnaire. As seen in our prior work [8], Veterans deployed to the SWA were asked to rate the frequency, duration, and intensity of potential exposures via a 0–4 point Likert-type scale. Exposures included 1) sand and dust, 2) smoke from burning trash, 3) exhaust and diesel fumes, 4) industrial air pollution.
Spirometry
All participants performed spirometry maneuvers prior to CPET in accordance with recommended guidelines [20,21], using a flow-sensing device (Cosmed Quark PFT; Rome, Italy) which was calibrated before each use. Spirometric variables are presented in their actual units and expressed as a percent of predicted [22] and included: forced vital capacity (FVC), forced expiratory volume (FEV1), and their ratio (FEV1/FVC). Abnormal results were defined as observed values of FEV1/FVC below the lower limit of normal as defined by Hankinson et al. [22].
Cardiopulmonary exercise testing
Participants performed a maximal effort CPET on a treadmill (Trackmaster) using the Bruce Protocol until volitional exhaustion [23]. Heart rate and rhythm (Cosmed T12x; Rome, Italy), as well as oxygen saturation were continuously monitored. Blood pressure was manually auscultated every 3 min during exercise and every 2 min into recovery. Perceived exertion (RPE; 6–20 scale) and dyspnea (Borg Breathlessness Scale; 0–10 scale) were measured every 2 min throughout exercise and at min 2-, 5- and 10 of recovery [24]. Pulmonary gas exchange and ventilation were measured breath-by-breath via an oronasal face mask interfaced with a metabolic cart (Cosmed Quark CPET).
A clinical exercise physiologist supervised all CPETs and ensured participant safety. Testing was terminated when end criteria were reached as judged by the test administrator or when participants were no longer able to maintain speed and grade despite verbal encouragement. Valid effort was defined as meeting two or more of the following criteria: 1) peak respiratory exchange ratio (RER) ≥ 1.1, 2) peak heart rate ≥ 85% of age-predicted maximum, 3) no change in the rate of oxygen consumption () < 2.1 ml∙min∙kg−1 over last min (
plateau), 4) RPE rating of ≥ 17, and/or 5) blood lactate level reaching sex- and age-related thresholds [25,26].
plateau was considered present if at least two of three clinical exercise physiologists who independently examined the CPET report ruled that a valid plateau was achieved.
Exercise data processing
Raw breath-by-breath data were visually inspected and averaged (30 sec. intervals) for offline analysis in MATLAB (v20.0, Mathworks; Natick, MA). Respiratory compensation point and ventilatory anaerobic threshold (VAT) were determined by lab personnel using the plot and the modified V-slope approach, respectively [27]. Most prioritized variables were directly measured during CPET which included rate of oxygen consumption (
), rate of carbon dioxide production (
), respiratory frequency (f R), tidal volume (VT), minute ventilation (
), respiratory exchange ratio (RER) and heart rate (HR). Since dyspnea and RPE were measured every 2 min during testing, these variables were exported individually by lab personnel based on the closest rating to target time. For example, if a subject reached 60% of their
during minute 4:30 of exercise, the dyspnea and RPE rating given at min 4 was used. Dyspnea and RPE ratings are only presented as %
.
Breathing reserve (BR) and ventilatory efficiency () were calculated to assess ventilatory limitations. BR was calculated using predicted maximal voluntary ventilation (MVV = FEV1 x 40; L/min) where
with values ≤ 15% considered abnormal [28]. Ventilatory efficiency was defined as the regression slope relating
to
slope from the start of exercise to respiratory compensation point if applicable [29].
slope values ≥ 35 were considered abnormal.
Statistical analysis
Statistical analyses were conducted in SPSS 26 (IBM Corp., Armonk, NY). All analyses were limited only to those participants who met criteria for valid effort. Group differences in participant characteristics, pulmonary function, and ventilatory limitations (BR, ,
) were analyzed using independent t-tests and Hedges’ d (d) effect sizes. Effect sizes of 0.25, 0.50, and 0.80 were interpreted as small, medium, and large, respectively. Normality was checked using the Kolmogorov-Smirnov test and non-normal data were analyzed using Mann-Whitney U. Chi-square or Fisher’s exact test was used to determine differences in groups when comparing categorical data.
For our primary analysis, separate repeated measures analysis of variance models (2 groups: deployed vs non-deployed at 6 relative intensities: 0%, 20%, 40%, 60%, 80%, and 100% ) were used to analyze select CPET variables (
,
,
, VT, fR, dyspnea, RPE, RER, HR). Degrees of freedom were adjusted (Greenhouse-Geisser) when the sphericity assumption was violated (Mauchly’s test of Sphericity). The magnitude of main and interaction effects was assessed with F-statistics and partial eta squared effect size (η2partial). Values of 0.01, 0.06, and 0.14 for η2partial were interpreted as small, medium, and large effects respectively.
Results
Participant characteristics
All 48 participants completed the CPET protocol. Of the 48 participants, 36 participants met criteria for valid effort (25 deployed, 11 non-deployed). The remaining 12 participants were excluded from the primary analytic sample (Fig 1). Demographics, self-reported health, and physical activity are reported in Table 1 (Fisher’s exact for sex, P = 1.00). The only significant between-group difference was the VR-36 PCS score (P = 0.048). There was moderate between-group difference characterized by worse physical health in the deployed group relative to the non-deployed group (d = -0.75; 95% CI: -1.48, -0.01). Self-reported respiratory symptoms are presented in Table 2. Deployed Veterans reported significantly worse respiratory health across all four categories examined (P<0.05) with effect size differences ranging from d = 0.98–2.02. Self-reported exposures are reported in Table 3. Regarding functional limitations, Fisher’s exact test indicated that the proportion of participants reporting limited function (rating of 3 or higher) did not significantly differ between groups—climbing upstairs: 16% vs 0%, P = 0.290; walk up a hill: 16% vs 0%, P = 0.290; Running 1 mile: 16% vs 9.1%, P = 1.00; walk 1 mile: 8% vs 0%, P = 1.00; walk ¼ mile: 0% vs 0%, P = 1.00).
Spirometry
Results from spirometry testing are presented in Table 4. Significant differences (P<0.05) were observed for the percent predicted for FVC (d = -1.02; 95% CI: -1.79, -0.26) and FEV1 (d = -1.00; 95% CI: -1.76, -0.23). Among deployed Veterans 23% had FEV1/FVC ratios below the LLN while only 9% for the non-deployed group (Fisher’s Exact Test P = 0.223).
Cardiopulmonary exercise testing
From the repeated measure tests, f R showed both a significant group (P = 0.001; η2partial = 0.26) and interaction (P = 0.022; η2partial = 0.10) effect. There was a significant group effect for dyspnea ratings (P = 0.011; η2partial = 0.18). Group and interaction effects were not observed for any other CPET parameter, but all variables had a significant time-effect (all P<0.001). Fig 2 shows mean values for , VT, and f R expressed as a percentage of
. Results from the repeated measures models are presented in Table 5. Mean (SD) for prioritized CPET parameters at each stage (i.e., rest, VAT, peak exercise) and expressed as a percentage of
are reported in Tables 6 & 7.
Ventilatory limitations
BR and slope results are presented in Table 8. Neither variable was significantly different between groups. Fisher’s exact test revealed that the proportion of participants exhibiting abnormal BR did not differ between deployed Veterans and non-deployed controls (4%/18%; P = 0.223). Similarly, no group differences were observed for abnormal
(8%/0%; P = 1.00).
Discussion
A growing recognition of the austere environmental conditions of SWA and deployment-related exposures (e.g., vapors, gases, dusts and fumes) has led to several studies exploring respiratory complaints of deployed Veterans [2–5,30]. Many of these studies are unable to identify a clear etiology for these complaints which we hypothesized may be due, in part, to the nature of resting pulmonary function testing and that assessments on exertion (i.e., CPET) may yield greater insight. In the present study, our deployed Veterans endorsed considerable exposures (Table 3) and substantially greater respiratory limitations (Table 2) than non-deployed controls despite not seeking treatment for their symptoms. Spirometric evaluation did demonstrate greater obstruction and CPET revealed alterations in breathing patterns among deployed Veterans. These findings are discussed in greater detail below.
Larger between-group differences were observed for fR and dyspnea relative to other CPET indices
The primary aim of this study was to evaluate the potential utility of CPET to provide physiological insight into respiratory symptoms reported by Veterans deployed to SWA (i.e., dyspnea). Specifically, we tested whether SWA deployment is associated with deficiencies in cardiorespiratory health by comparing physiological and perceptual responses to maximal exercise between deployed Veterans and non-deployed controls. After restricting our analytic dataset to 36 participants (25 deployed, 11 non deployed) meeting criteria for a valid peak effort (Fig 1), we observed minimal between-group differences for a majority of CPET variables (,
,
, VT, RER, and HR). However, we observed moderate-large group (η2partial = 0.26) and group-by-time interaction (η2partial = 0.096) effects for fR. As shown in Fig 2, these findings are characterized by slower fR and a greater change over time in deployed Veterans relative to non-deployed controls. Additionally, a large group effect was observed for exertional dyspnea such that deployed Veterans exhibited higher ratings than non-deployed controls (η2partial = 0.18). Furthermore, the findings do not appear to be confounded by ventilatory limitations, as indicated by non-significant group differences in BR (Table 8).
It is noteworthy that spirometry results showed limitations (FEV1/FVC < LLN) for 5 deployed Veterans (~23%) and 1 non-deployed control (~9%). To ensure that any observed effects from our study were not related to potential restrictive or obstructive lung patterns, all analyses were repeated excluding participants who had FEV1/FVC < LLN. Overall, similar findings were observed in the restricted dataset (Tables 9–15). Despite limiting the dataset, deployed Veterans showed distinct breathing patterns where they employed deeper but slower breaths during exercise. These differences were more visible at greater exercise intensities. In our estimation, these collective symptom and pulmonary function results indicate that ventilatory mechanical limitations do not explain the respiratory limitations experienced by our sample of deployed Veterans.
Our findings can be interpreted in the context of prior research involving both healthy adults and deployment-related illnesses such as Gulf War Illness (GWI). Consistent with earlier work which found that VT is determined more by metabolic factors than fR [31–34], a study of healthy adults found that fR, but not VT, responds rapidly to changes in workload during high-intensity cycling and recovery, is independent from metabolic factors (,
), and is strongly associated with RPE [35]. Further, our prior study of Veterans with GWI found altered breathing patterns in Veterans with GWI, as indicated by higher VT and lower fR compared to non-symptomatic controls [13]. Additionally, group differences in fR were larger than VT, suggesting that
was primarily driven by fR in symptomatic Veterans. Integrating these prior studies with the present study, our observation of slower fR in deployed Veterans may represent a centrally-mediated, learned strategy to mitigate dyspnea symptoms during exercise (i.e., breathing slower may help decrease feelings of breathlessness). However, it is important to note that we did not collect data on breathing patterns prior to development of dyspnea symptoms, so longitudinal CPET studies assessing pre- and post-deployment health are clearly needed to establish temporal sequence.
Respiratory frequency was positively associated with dyspnea ratings in deployed Veterans
Following our observation of differential fR patterns between deployed and non-deployed participants, we conducted exploratory correlational analyses which revealed that dyspnea ratings were significantly associated with fR at 80% (r = 0.58) and 100% (r = 0.41) of , but only in deployed Veterans (Figs 3 and 4). The design of the present study does not lend itself to determining whether there is a mechanistic link between fR and dyspnea, but we are not the only group to observe an association between these two variables. For instance, in healthy young adults who completed a staged cycle ergometry protocol (50W/4min), Tsukada reported that the threshold at which fR becomes tachypneic is preceded by and associated with the point at which exertional dyspnea begins to rapidly increase [36]. The investigators speculated that unpleasantness accompanied by dyspnea reaches a level which induces emotional respiratory reactions to stimulate a tachypneic breathing pattern. However, our findings are somewhat counterfactual to that interpretation. That is, despite reporting higher dyspnea ratings throughout the CPET, deployed Veterans had slower fR values than non-deployed Veterans at every timepoint (Table 6, Fig 2), as also observed in our prior work involving Veterans with Gulf War Illness [13]. Given that Tsukada focused on healthy adults whereas we focused on Veterans with deployment related exposures, perhaps people who experience significant respiratory symptoms on a day-to-day basis are less susceptible to dyspnea-driven increases in fR because they are more familiar with the experience of dyspnea than otherwise healthy people (Table 2). This hypothesis could be tested by studying the effect of experimentally manipulated dyspnea on fR in a direct comparison of healthy and symptomatic Veterans.
Prior reporting of CPET indices in post-911 SWA Veterans is limited
Multiple other studies have conducted CPET in deployed SWA military personnel and Veterans [1,3,7,11,12]; however, analyses have focused primarily on traditional parameters (e.g., peak exercise) and do not consider dynamic exercise ventilation patterns. For instance, two separate studies by Morris and colleagues report numerous CPET values but limited to two timepoints: and VAT [3,7]. Interestingly, authors observed increased peak fR among those with dyspnea relative to controls (Mean (SD): 50.2 (12.4) vs 44.5 (6.7)) but it is unclear whether fR differences persisted at submaximal intensities. Moreover, other studies that have included CPET in their analyses [1] only presented
and percent abnormal for
,
,
, and VAT. Similar to the present study, these previously performed studies rarely identify between-group differences when restricting CPET analyses to traditional indices. It should be noted that unlike the present sample comprised of non-treatment seeking Veterans, previously published studies in military personnel and Veterans underwent CPET as part of a clinical evaluation for respiratory complaints [1,3–5,12,37]. Although the present study sample was not referred for clinical evaluation, the deployed Veteran group endorsed considerable respiratory symptom burden (Table 2).
Limitations and future directions
This study was not without limitations. First, it is important to acknowledge the cross-sectional nature of our design. Despite excluding participants who reported having asthma prior to deployment, we did not directly measure respiratory health in this sample prior to SWA deployment. Therefore, studies that evaluate respiratory health and CPET parameters prior to and following deployment are needed to substantiate and extend our findings. Second, in light of emerging evidence arguing for a multidimensional model of dyspnea measurement [38], it is possible that there were certain aspects of dyspnea that were not captured by our 0–10 Borg Breathlessness Scale such as an affective component of dyspnea. Given the strong relationship between fR and emotion [39], and that we found greater fR in deployed participants, future attempts to explore the relationship between dyspnea and fR may also consider measuring the affective as well as sensory components of dyspnea. Third, although we did not observe signs of ventilatory limitations via examination of BR, alternative methods such as using serial inspiratory capacity maneuvers during exercise may have revealed dynamic respiratory mechanical abnormalities not observed by examining BR alone [10]. Thus, future studies should consider using serial inspiratory capacity maneuvers in addition to BR to increase confidence that ventilatory limitations are not contributing to dyspnea ratings [10]. Fourth, it is possible that there were smaller CPET-related differences between deployed and non-deployed participants which were not observed because of statistical power. Although we started with a larger number of participants at the outset of this study, it was important to restrict our analysis only to those participants who met valid effort criteria as our prior work involving Veterans with unexplained fatigue has shown that the ability to detect smallest real differences is sometimes affected by whether or not participants met max criteria [40]. Nevertheless, our findings should be viewed as preliminary, hypothesis generating results that warrant confirmation in a larger sample.
Conclusion
In our sample, Veterans deployed to SWA exhibit reduced fR and greater dyspnea during maximal exercise relative to non-deployed controls. Further, fR is positively associated with dyspnea ratings at 80% and 100% of in deployed Veterans but not in non-deployed controls. These findings provide support for a potential association between deployment to SWA and cardiorespiratory health. In addition, our findings highlight the utility of incorporating CPET for the evaluation of exertional dyspnea beyond that of traditional peak indices to investigate the dynamic behavior of exercise ventilation.
Acknowledgments
The authors would like to thank the volunteers who participated in this study as well as data collection and analysis support from Bishoy Samy and Nancy Eager. This study was registered on clinicaltrials.gov (NCT01754922). The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government.
References
- 1. Krefft SD, Wolff J, Zell-Baran L, Strand M, Gottschall EB, Meehan R, et al. Respiratory Diseases in Post-9/11 Military Personnel Following Southwest Asia Deployment. J Occup Environ Med. 2020;62. pmid:31977922
- 2. Falvo MJ, Osinubi OY, Sotolongo AM, Helmer DA. Airborne Hazards Exposure and Respiratory Health of Iraq and Afghanistan Veterans. Epidemiol Rev. 2015;37: 116–130. pmid:25589052
- 3. Morris MJ, Dodson DW, Lucero PF, Haislip GD, Gallup RA, Nicholson KL, et al. Study of Active Duty Military for Pulmonary Disease Related to Environmental Deployment Exposures (STAMPEDE). Am J Respir Crit Care Med. 2014;190: 77–84. pmid:24922562
- 4. Morris MJ, Skabelund AJ, Rawlins FA, Gallup RA, Aden JK, Holley AB. Study of Active Duty Military Personnel for Environmental Deployment Exposures: Pre- and Post-Deployment Spirometry (STAMPEDE II). Respir Care. 2019;64: 536–544. pmid:30622173
- 5. Morris MJ, Walter RJ, McCann ET, Sherner JH, Murillo CG, Barber BS, et al. Clinical Evaluation of Deployed Military Personnel With Chronic Respiratory Symptoms. Chest. 2020;157: 1559–1567.
- 6.
National Academies, Sciences, and Engineering; Health and Medicine Division; Board on Population Health and Public Health Practice; Committee on the Respiratory Health Effects of Airborne Hazards Exposures in the Southwest Asia Theater of Military Operations. Respiratory Health Effects of Airborne Hazards Exposures in the Southwest Asia Theater of Military Operations. Washington (DC): National Academies Press (US); 2020. https://www.ncbi.nlm.nih.gov/books/NBK562789/.
- 7. Morris MJ, Grbach VX, Deal LE, Boyd SYN, Morgan JA, Johnson JE. Evaluation of exertional dyspnea in the active duty patient: the diagnostic approach and the utility of clinical testing. Mil Med. 2002;167: 281–288. pmid:11977877
- 8. Klein-Adams JC, Sotolongo AM, Serrador JM, Ndirangu DS, Falvo MJ. Exercise-Induced Bronchoconstriction in Iraq and Afghanistan Veterans With Deployment-Related Exposures. Mil Med. 2020;185: e389–e396. pmid:31889186
- 9. Parshall MB, Schwartzstein RM, Adams L, Banzett RB, Manning HL, Bourbeau J, et al. An official American Thoracic Society statement: update on the mechanisms, assessment, and management of dyspnea. Am J Respir Crit Care Med. 2012;185: 435–452. pmid:22336677
- 10. Neder JA, Berton DC, Marillier M, Bernard A-C, O’Donnell DE. Inspiratory Constraints and Ventilatory Inefficiency Are Superior to Breathing Reserve in the Assessment of Exertional Dyspnea in COPD. COPD J Chronic Obstr Pulm Dis. 2019;16: 174–181. pmid:31272243
- 11. King MS, Eisenberg R, Newman JH, Tolle JJ, Harrell FE, Nian H, et al. Constrictive Bronchiolitis in Soldiers Returning from Iraq and Afghanistan. N Engl J Med. 2011;365: 222–230. pmid:21774710
- 12. Holley AB, Mabe DL, Hunninghake JC, Collen JF, Walter RJ, Sherner JH, et al. Isolated Small Airway Dysfunction and Ventilatory Response to Cardiopulmonary Exercise Testing. Respir Care. 2020;65: 1488. pmid:32234772
- 13. Lindheimer JB, Cook DB, Klein-Adams JC, Qian W, Hill HZ, Lange G, et al. Veterans with Gulf War Illness exhibit distinct respiratory patterns during maximal cardiopulmonary exercise. Weston KL, editor. PLOS ONE. 2019;14: e0224833. pmid:31714907
- 14. Committee Members, Gibbons RJ, Balady GJ, Timothy Bricker J, Chaitman BR, Fletcher GF, et al. ACC/AHA 2002 Guideline Update for Exercise Testing: Summary Article: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1997 Exercise Testing Guidelines). Circulation. 2002;106: 1883–1892. pmid:12356646
- 15. Ranu H, Wilde M, Madden B. Pulmonary function tests. Ulster Med J. 2011;80: 84–90. pmid:22347750
- 16. Craig CL, Marshall AL, Sjostrom M, Bauman AE, Booth ML, Ainsworth BE, et al. International physical activity questionnaire: 12-country reliability and validity. Med Sci Sports Exerc. 2003;35: 1381–1395. pmid:12900694
- 17. Kazis LE. The Veterans SF-36 Health Status Questionnaire: Development and Application in the Veterans Health Administration. 2000;5: 18.
- 18. Barr JT, Schumacher GE, Freeman S, LeMoine M, Bakst AW, Jones PW. American translation, modification, and validation of the St. George’s Respiratory Questionnaire. Clin Ther. 2000;22: 1121–1145. pmid:11048909
- 19. Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A self-complete measure of health status for chronic airflow limitation. The St. George’s Respiratory Questionnaire. Am Rev Respir Dis. 1992;145: 1321–1327. pmid:1595997
- 20. Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R, et al. Interpretative strategies for lung function tests. Eur Respir J. 2005;26: 948. pmid:16264058
- 21. Miller MR. Standardisation of spirometry. Eur Respir J. 2005;26: 319–338. pmid:16055882
- 22. Hankinson JL, Odencrantz JR, Fedan KB. Spirometric Reference Values from a Sample of the General U.S. Population. Am J Respir Crit Care Med. 1999;159: 179–187. pmid:9872837
- 23. Bruce RA, Blackmon JR, Jones JW, Strait G. Exercising testing in adult normal subjects and cardiac patients. Pediatrics. 1963;32: 742–756. pmid:14070531
- 24. Borg GAV. Psychophysical bases of perceived exertion. Med Sci Sports Exerc. 1982;14: 377–381. pmid:7154893
- 25. Edvardsen E, Hem E, Anderssen SA. End Criteria for Reaching Maximal Oxygen Uptake Must Be Strict and Adjusted to Sex and Age: A Cross-Sectional Study. PLOS ONE. 2014;9: e85276. pmid:24454832
- 26.
ACSM’s guidelines for exercise testing and prescription. 9th Edition. Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins Health; 2014.
- 27. Beaver WL, Wasserman K, Whipp BJ. A new method for detecting anaerobic threshold by gas exchange. J Appl Physiol Bethesda Md 1985. 1986;60: 2020–2027. pmid:3087938
- 28. Kaminsky LA, Harber MP, Imboden MT, Arena R, Myers J. Peak Ventilation Reference Standards from Exercise Testing: From the FRIEND Registry. Med Sci Sports Exerc. 2018;50: 2603–2608. pmid:30095740
- 29.
Wasserman K, Hansen JE, Sue DY, Stringer WW, Sietsema KE, Sun X-G, et al. Principles of Exercise Testing and Interpretation: Including Pathophysiology and Clinical Applications. 4th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2004.
- 30. Garshick E, Abraham JH, Baird CP, Ciminera P, Downey GP, Falvo MJ, et al. Respiratory Health after Military Service in Southwest Asia and Afghanistan. An Official American Thoracic Society Workshop Report. Ann Am Thorac Soc. 2019;16: e1–e16. pmid:31368802
- 31. Thornton JM, Guz A, Murphy K, Griffith AR, Pedersen DL, Kardos A, et al. Identification of higher brain centres that may encode the cardiorespiratory response to exercise in humans. J Physiol. 2001;533: 823–836. pmid:11410638
- 32. Bell HJ, Duffin J. Rapid increases in ventilation accompany the transition from passive to active movement. Respir Physiol Neurobiol. 2006;152: 128–142. pmid:16153897
- 33. Nicolò A, Marcora SM, Sacchetti M. Respiratory frequency is strongly associated with perceived exertion during time trials of different duration. J Sports Sci. 2016;34: 1199–1206. pmid:26503587
- 34. Nicolò A, Bazzucchi I, Haxhi J, Felici F, Sacchetti M. Comparing continuous and intermittent exercise: an “isoeffort” and “isotime” approach. PloS One. 2014;9: e94990. pmid:24736313
- 35. Nicolò A, Marcora SM, Bazzucchi I, Sacchetti M. Differential control of respiratory frequency and tidal volume during high-intensity interval training. Exp Physiol. 2017;102: 934–949. pmid:28560751
- 36. Tsukada S, Masaoka Y, Yoshikawa A, Okamoto K, Homma I, Izumizaki M. Coupling of dyspnea perception and occurrence of tachypnea during exercise. J Physiol Sci. 2017;67: 173–180. pmid:27117877
- 37. Szema AM, Peters MC, Weissinger KM, Gagliano CA, Chen JJ. New-onset asthma among soldiers serving in Iraq and Afghanistan. Allergy Asthma Proc. 2010;31: 67–71. pmid:20929596
- 38. Lansing RW, Gracely RH, Banzett RB. The multiple dimensions of dyspnea: Review and hypotheses. Respir Physiol Neurobiol. 2009;167: 53–60. pmid:18706531
- 39. Homma I, Masaoka Y. Breathing rhythms and emotions: Breathing and emotion. Exp Physiol. 2008;93: 1011–1021. pmid:18487316
- 40. Lindheimer JB, Alexander T, Qian W, Klein‐Adams JC, Lange G, Natelson BH., et al. An analysis of 2‐day cardiopulmonary exercise testing to assess unexplained fatigue. Physiol Rep. 2020;8. pmid:32889791