Sex Differences in Exercise-Induced Bronchoconstriction in Athletes: A Systematic Review and Meta-Analysis

Exercise-induced bronchoconstriction (EIB) is a common complication of athletes and individuals who exercise regularly. It is estimated that about 90% of patients with underlying asthma (a sexually dimorphic disease) experience EIB; however, sex di erences in EIB have not been studied extensively. With the goal of better understanding the prevalence of EIB in males and females, and because atopy has been reported to occur at higher rates in athletes, in this study, we investigated sex di erences in EIB and atopy in athletes. A systematic literature review identi ed 60 studies evaluating EIB and/or atopy in post-pubertal adult athletes (n=7501). Collectively, these studies reported: (1) a 23% prevalence of EIB in athletes; (2) a higher prevalence of atopy in male vs. female athletes; (3) a higher prevalence of atopy in athletes with EIB; (4) a signi cantly higher rate of atopic EIB in male vs. female athletes. Our analysis indicates that the physiological changes that occur during exercise may di erentially a ect male and female athletes, and suggest an interaction between male sex, exercise, and atopic status in the course of EIB. Understanding these sex di erences is important to provide personalized management plans to athletes with underlying asthma and/or atopy. Keywords: in ammation; atopy; exercise-induced asthma; exercise-induced bronchoconstriction; sex di erences 1. Introduction Asthma is one of the most common chronic non-communicable diseases of the airways, a ecting about 339 million people worldwide [1]. The global prevalence of self-reported and physician-diagnosed asthma in adults is 4.3% (95% CI 4.2–4.4), with wide variation among countries [2]. Asthma is generally characterized by airway smooth muscle constriction (bronchospasm), excessive in ammation of

di erences 1. Introduction Asthma is one of the most common chronic non-communicable diseases of the airways, a ecting about 339 million people worldwide [1]. The global prevalence of self-reported and physician-diagnosed asthma in adults is 4.3% (95% CI 4.2–4.4), with wide variation among countries [2]. Asthma is generally characterized by airway smooth muscle constriction (bronchospasm), excessive in ammation of the airway, and increased mucus production, although it presents in a variety of phenotypes and endotypes, ranging from mild and intermittent to severe and uncontrolled [3]. The diagnosis of asthma is determined by the history of respiratory symptoms, such as wheezing, shortness of breath, chest tightness, and cough, that vary over time and in intensity, together with variable expiratory air ow limitations [4,5]. Asthma is a heterogeneous disease, usually characterized by chronic in ammation. The clinical course of asthma is in uenced by several factors, including genetics [6], environmental and occupational exposures [7], sex and gender [8], and hormones [9]. Atopy is also frequently associated with asthma [10]. Di erent from an allergy (i.e., the exaggerated immune response to a foreign antigen regardless of mechanism), atopy is characterized by an exaggerated IgE-mediated response to an allergen. Worldwide, 80% of childhood asthma and over 50% of adult asthma has been reported to be Int. J. Environ. Res. Public Health2020,17, 7270; doi:10.3390 /ijerph17197270 /journal/ijerph

Int. J. Environ. Res. Public Health2020,17, 7270 2 of 17 atopic [11]. In the United States, 56.3% of asthma cases have been attributed to atopy, a percentage that is greater among male patients than female patients [12]. Exercise and physical exertion are some of the most common triggers of bronchospasm in patients with asthma [13,14]. Bronchial hyperreactivity, a basic feature of bronchial asthma, occurs more often in athletes than non-athletes, especially in swimmers and winter sports athletes [15,16]. Exercise-induced respiratory symptoms usually involve acute narrowing of the airways that occurs during or after exercise and include exercise-induced bronchoconstriction (EIB) [17]. EIB is de ned as the acute onset of bronchoconstriction occurring during or immediately after exercise [18]. Although EIB has been estimated to occur in up to 90% of patients with underlying asthma, it also occurs in subjects with no prior history of asthma and no symptoms outside of exercise [19]. Similarly, there is a subset of patients who have only exercise-induced asthma, but not chronic daily asthma [18]. Overall, while the epidemiology of asthma has been widely reported and studied worldwide, the epidemiology of exercise-induced asthma and EIB has not been well described. Sex and gender di erences in the incidence, prevalence, and severity of lung diseases have been noted for years [20]. The terms “sex” and “gender” are oftentimes used interchangeably in research studies, although they represent di erent concepts. “Sex” refers to the underlying biological di erences between males and females, including sex organs, XY chromosomes, and expression of endogenous hormones, while “gender” is a social construct that imparts roles and behaviors as masculine or feminine within the framework of historical or cultural contexts. The recent implementation of regulations and policies encouraging the incorporation of sex as a biological variable in research studies has permitted the identi cation and characterization of sex-speci c mechanisms of lung diseases, including asthma, across the lifespan. Among children, the prevalence of asthma is higher in males than in females [21]. However, after puberty, the prevalence is about 20% higher in females than males, indicating a potential contribution of sex hormones [22].

a biological variable in research studies has permitted the identi cation and characterization of sex-speci c mechanisms of lung diseases, including asthma, across the lifespan. Among children, the prevalence of asthma is higher in males than in females [21]. However, after puberty, the prevalence is about 20% higher in females than males, indicating a potential contribution of sex hormones [22]. Regarding the response to exercise, research studies evaluating sex di erences have reported that the male and female body di er in cardiovascular, respiratory, thermoregulatory, metabolic, and neuromuscular responses that have clear implications for understanding sex-speci c adaptations to exercise for athletic performance and overall health [23]. Gender, on the other hand, can potentially in uence an individual's behavior or preference towards a speci c sport or physical depending on societal beliefs. Although asthma has been widely reported to be more prevalent and severe in adult females than males [21,22], very few studies to date have addressed sex di erences in EIB and/or the overall e ects of exercise in male and female patients with asthma. One study reported that female adolescents, but not males, with EIB experience a lower health-related quality of life and poorer lung function than those without EIB [24]. Others reported that female athletes exhibit more severe symptoms of EIB than males, especially in the luteal phase of the menstrual cycle [25]. However, there is still no consensus in the literature on an established sexual dimorphism for EIB, nor studies addressing the mechanisms underlying potential sex di erences in EIB prevalence and/or severity. Because minute ventilation rises with exercise [14], EIB likely results from changes in airway physiology triggered by the large volume of relatively cool, dry air inhaled during vigorous activity [26]. This is supported by research ndings concluding that the main determinant of the occurrence and degree of bronchoconstriction is not the type of exercise, but rather the ventilation demand and humidity of the inspired air during exercise [27–29]. Here, we have conceptualized EIB as the acute onset of bronchoconstriction occurring during or immediately after exercise, independently of a subject's underlying asthma. This concept

by research ndings concluding that the main determinant of the occurrence and degree of bronchoconstriction is not the type of exercise, but rather the ventilation demand and humidity of the inspired air during exercise [27–29]. Here, we have conceptualized EIB as the acute onset of bronchoconstriction occurring during or immediately after exercise, independently of a subject's underlying asthma. This concept is an accurate re ection of the disease's underlying pathophysiology. The purpose of this review was to evaluate the overall prevalence of EIB and atopy in male and female athletes. We examined the available literature on sex di erences in EIB in athletes and recreationally active individuals, outlining epidemiological data and results from clinical studies. We identi ed studies conducted in adult athletes and determined the prevalence of EIB, as well as the relationship between asthma, EIB, and atopy in male and female athletes.

Int. J. Environ. Res. Public Health2020,17, 7270 3 of 17 2. Materials and Methods 2.1. Literature Search 2.1.1. Databases and Key Terms Searched The literature search was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [30]. Studies were identi ed by searching PubMed/MEDLINE Complete, PubMed Central, and Google Scholar, up to July 2020. Search terms, phrases, and Medical Subject Headings (MeSH) were selected based on the purpose of the review and inclusion criteria. We used the search parameters: (`exercise' OR `athlete') AND (`gender' OR `sex') AND (`asthma' OR `bronchoconstriction') AND (`atopy'). 2.1.2. Inclusion Criteria The literature search was limited to human studies that were research-data based and published in only English language. Studies were selected if research study subjects were 12 years old and older, and athletes or recreational athletes were training for 2 days/week or 4 h/week in aerobic activities. Selected subjects' training conditions were water sports (e.g., swimming, water polo), winter sports (e.g., cross-country skiing, biathlon, skeleton, alpine skiing, and ski cross), and other sports (including, but not limited to, running, speed skating, curling, handball, judo, triathlon, football, cycling, beach volley, rowing, athletics, sailing, badminton, canoeing, curling, equestrian, taekwondo, auto-racing, billiards, paragliding, rugby, tennis, roller hockey, kickboxing, fencing, basketball, or golf). 2.1.3. Search Process and Study Selection The literature search was conducted using both authors' university library websites by entering search terms in the databases. Records were de-duplicated using the built-in mechanisms of the university library services and further completed manually. Articles were then assessed by their titles and abstracts for inclusion. Final selections were determined after full reading of articles. Each article was appraised based on the following ve criteria: (1) relevance of the sampling strategy to address the research question, (2) representation of the sample on the target population, (3) appropriateness of the measurements, (4) risk of nonresponse bias, and (5) suitability of statistical analysis to answer the research question. 2.2. Data Extraction and Analysis The following information was extracted from the studies: the rst author of the study, the year of publication, the country of the study conducted, the purpose of

of the sample on the target population, (3) appropriateness of the measurements, (4) risk of nonresponse bias, and (5) suitability of statistical analysis to answer the research question. 2.2. Data Extraction and Analysis The following information was extracted from the studies: the rst author of the study, the year of publication, the country of the study conducted, the purpose of the study, data on the sample size, details of the intervention, study quality, and measured outcomes. Main outcomes included EIB prevalence through questionnaire and/or pulmonary function testing (PFT). In addition, atopic status and self-reporting exercise-induced asthma-like symptoms in female (F) and male (M) athletes were extracted in all studies where these variables were reported. Atopy was de ned as skin-test reactivity (skin prick test result). EIB was de ned as a decrease of at least 15% in forced expiratory volume in one second (FEV1) vs. baseline at di erent timepoints after exercise spirometry or eucapnic voluntary hyperpnea (EVH), in addition to mannitol bronchoprovocation test or methacholine challenge; or having a prior medical diagnosis of EIB, respectively. 3. Results A ow chart of the literature search is shown in Figure. The search string returned 1456 potentially relevant article citations. After systematically reviewing all the abstracts, 776 irrelevant studies and 508 duplicate papers were removed. Two independent investigators screened the remaining 172 full-text studies for eligibility and found that 35% of articles (60 studies including 7501 subjects; age range 12–67 years) met the inclusion criteria. These were categorized according to whether they

Int. J. Environ. Res. Public Health2020,17, 7270 4 of 17 reported sex di erences in measured outcomes, and/or included male and female participants in the research design (Figure).Int. J. Environ. Res. Public Health 2020, 17, x 4 of 17 Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram of literature search and selection process. Figure 2. Screening process and classification of articles by sex reporting. RCT: randomized controlled trial; CT: clinical trial. 3.1. Prevalence of EIB in Athletes Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) ow diagram of literature search and selection process. 3.1. Prevalence of EIB in Athletes To quantify the general prevalence of asthma and EIB in athletes, we rst categorized the studies by method used for EIB diagnosis. These included exercise challenge [31,32], EVH with dry air [33], and EVH in combination with a bronchoprovocation test with mannitol or methacholine. We found that the majority of studies (43%), collectively enrolling 1829 subjects, used an exercise challenge (Figure), while 20% of the reviewed studies (n=829 subjects) used EVH with dry air alone, or in combination with a bronchoprovocation test. In addition, 9% percent of studies used a bronchoprovocation challenge (n=474 subjects), and 9% (n=921 subjects) used self-reporting data (questionnaires) only. The remaining 20% of studies used a combination of these methods (n=1050 subjects) and are further categorized in Figure. Overall, we found that the prevalence of EIB was reported in a total of 35 of the 60 reviewed studies, using a combination of the methods listed above. The studies, main ndings, and ratio of male and female enrolled subjects are summarized in Table 34–68]. Collectively, these studies enrolled 5103 athletes and reported a diagnosis of EIB in 1153 subjects. This corresponds to a general EIB prevalence of 23% (1153/5103).

Int. J. Environ. Res. Public Health2020,17, 7270 5 of 17Int. J. Environ. Res. Public Health 2020, 17, x 4 of 17 Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram of literature search and selection process. Figure 2. Screening process and classification of articles by sex reporting. RCT: randomized controlled trial; CT: clinical trial. 3.1. Prevalence of EIB in Athletes Figure 2. Screening process and classi cation of articles by sex reporting. RCT: randomized controlled trial; CT: clinical trial.Int. J. Environ. Res. Public Health 2020, 17, x 5 of 17 To quantify the general prevalence of asthma and EIB in athletes, we first categorized the studies by method used for EIB diagnosis. These included exercise challenge [31,32], EVH with dry air [33], and EVH in combination with a bronchoprovocation test with mannitol or methacholine. We found that the majority of studies (43%), collectively enrolling 1829 subjects, used an exercise challenge (Figure 3), while 20% of the reviewed studies (n = 829 subjects) used EVH with dry air alone, or in combination with a bronchoprovocation test. In addition, 9% percent of studies used a bronchoprovocation challenge (n = 474 subjects), and 9% (n = 921 subjects) used self-reporting data (questionnaires) only. The remaining 20% of studies used a combination of these methods (n = 1050 subjects) and are further categorized in Figure 3. Overall, we found that the prevalence of EIB was reported in a total of 35 of the 60 reviewed studies, using a combination of the methods listed above. The studies, main findings, and ratio of male and female enrolled subjects are summarized in Table 1 [34–68]. Collectively, these studies enrolled 5103 athletes and reported a diagnosis of EIB in 1153 subjects. This corresponds to a general EIB prevalence of 23% (1153/5103). Figure 3. Diagnostic tests used to determine exercise induced bronchoconstriction in selected articles. EVH: eucapnic voluntary hyperpnea. Table 1. Prevalence of exercise-induced bronchoconstriction (EIB) among male and female athletes. Author, Year Method for EIB Diagnosis Study Population (n = subjects), Sex Ratio EIB Prevalence Ahad, Sandila, and Siddiqui, 2004 [34] Exercise challenge Pakistani

a general EIB prevalence of 23% (1153/5103). Figure 3. Diagnostic tests used to determine exercise induced bronchoconstriction in selected articles. EVH: eucapnic voluntary hyperpnea. Table 1. Prevalence of exercise-induced bronchoconstriction (EIB) among male and female athletes. Author, Year Method for EIB Diagnosis Study Population (n = subjects), Sex Ratio EIB Prevalence Ahad, Sandila, and Siddiqui, 2004 [34] Exercise challenge Pakistani hockey players (n = 27) Male only 19% Ahad, Sandila, Siddiqui, and Ahmed, 2003 [35] Exercise challenge Pakistani athletes (n = 179) Male only 7% Allen et al., 2019 [36] EVH 1 Recreational athletes (n = 180) (120:60) M:F 37% Ansley, Kippelen, Dickinson, and Hull, 2012 [37] EVH and Bronchoprovocation Test (dry powder mannitol) UK soccer players (n = 65) Male only 51% Becerril-Ángeles et al., 2017 [38} Exercise challenge Mexican high school and college athletes of summer sports (n = 208) (115:93) M:F 7.2% Figure 3.Diagnostic tests used to determine exercise induced bronchoconstriction in selected articles. EVH: eucapnic voluntary hyperpnea.

Int. J. Environ. Res. Public Health2020,17, 7270 6 of 17 Table 1.Prevalence of exercise-induced bronchoconstriction (EIB) among male and female athletes. Author, Year Method for EIB Diagnosis Study Population ( n=subjects), Sex Ratio EIB Prevalence Ahad, Sandila, and Siddiqui, 2004 [34] Exercise challenge Pakistani hockey players (n=27) Male only 19% Ahad, Sandila, Siddiqui, and Ahmed, 2003 [35] Exercise challenge Pakistani athletes (n=179) Male only 7% Allen et al., 2019 [36] EVH 1 Recreational athletes (n=180) (120:60) M:F 37% Ansley, Kippelen, Dickinson, and Hull, 2012 [37] EVH and Bronchoprovocation Test (dry powder mannitol) UK soccer players (n=65) Male only 51% Becerril-ngeles et al., 2017 [38] Exercise challenge Mexican high school and college athletes of summer sports (n=208) (115:93) M:F 7.2% Bonini et al., 2015 [39] Exercise challenge and Bronchoprovocation Test (dry powder mannitol or methacholine) Italian Olympic Delegation at Summer (Sydney 2000, Beijing 2008, and London 2012) and Winter (Vancouver 2010) Olympics (n=659) (441:218) M:F 14.7% Bougault, Turmel, and Boulet, 2010 [40] EVH and Bronchoprovocation Test (dry powder methacholine) Swimmers and winter sport athletes (n=45 in each group) (39:51) M:F 75% in swimmers 40% in winter sport athletes Burnett, Burns, Merritt, Wick, and Sharpe, 2016 [41] Exercise challenge 80 college athletes (56:24) M:F 42.5% Burnett, Vardiman, Deckert, Ward, and Sharpe, 2016 [42] Questionnaire 196 college athletes (56:140) M:F 28.6% Couillard et al., 2014 [43] Questionnaire, EVH and Bronchoprovocation Test (dry powder methacholine) 130 athlete swimmers (n=51 swimmers,n=10 synchronized swimmers), winter athletes (n=30 cross-country skiers,n=11 speed skaters training outdoors,n=9 biathletes), other endurance sports athletes (n=10 triathletes,n=7 cyclists,n=2 canoe-kayakers) (65:65) M:F 51% Couto et al., 2015 [44] Bronchoprovocation Test (dry powder mannitol or methacholine) Portuguese and Norwegian athletes training at high-competitive levels (national, international, or Olympic teams) (n=324) (107:43) M:F 46.2% Dickinson, McConnell, and Whyte, 2011 [45] EVH Elite British athletes (n=228) Sex not reported 34% Durand et al., 2005 [46] Exercise challenge Ski-mountaineering athletes (n=31) (28:3) M:F 48.3 % Hallstrand et al., 2002 [47] Exercise challenge Adolescents participating in organized sports from three suburban high schools (n=256) (136:120) M:F 9.4% Hunt et al., 2017 [48] Exercise challenge N=92 players from three senior

and Whyte, 2011 [45] EVH Elite British athletes (n=228) Sex not reported 34% Durand et al., 2005 [46] Exercise challenge Ski-mountaineering athletes (n=31) (28:3) M:F 48.3 % Hallstrand et al., 2002 [47] Exercise challenge Adolescents participating in organized sports from three suburban high schools (n=256) (136:120) M:F 9.4% Hunt et al., 2017 [48] Exercise challenge N=92 players from three senior inter-county hurling teams Male only 9.8% Kippelen, Caillaud, Coste, Godard, and Pr²faut, 2004 [49] Exercise challenge n=97 athletes Male only 5.3% Kukafka et al., 1998 [50] Exercise challenge High school football players (n=238) Male only 9% Langdeau et al., 2009 [51] Bronchoprovocation Test (dry powder methacholine) n=100 athletes (65:35) M:F AHR higher in females (60%) vs. males (21.5%), p<0.0001 Leuppi, Kuhn, Comminot, and Reinhart, 1998 [52] Bronchoprovocation Test (dry powder methacholine) Elite ice hockey players (n=26) and oorball players (n=24) Male only 34.6% (ice hockey); 20.8% ( oorball players) Levai et al., 2016 [53] EVH 38 boxers (33:5) M:F 44 swimmers (25:19) M:F 68% (elite swimmers); 8% (boxers) Lund, Pedersen, Larsson, and Backer, 2009 [54] Questionnaire 329 elite athletes (198:131) M:F 55% Molphy et al., 2014 [55] EVH Recreationally active individuals ( n=136) 13.2% Norqvist, Eriksson, Söderström, Lindberg, and Stenfors, 2015 [56] Questionnaire n=402 Swedish elite skiers, orienteers, and former Olympic athletes (cross-country and biathlon) (218:184) M:F 11% Ostho et al., 2013 [57] EVH and Bronchoprovocation Test (dry powder mannitol) n=44 athletes aiming to participate at the 2008 Beijing Paralympic Games (30:14) M:F 20% Parsons et al., 2012 [58] EVH n=144 athletes from six di erent varsity sports at a large National Collegiate Athletic Association Division I collegiate athletic program (79:65) M:F 3% Pedersen, Winther, Backer, Anderson, and Larsen, 2008 [59] EVH and Bronchoprovocation Test (dry powder methacholine) 16 elite swimmers Female only 50%

The study analyzes the prevalence of exercise-induced bronchoconstriction in male and female athletes.