Emerging Comorbidities in Adult Asthma: Risks, Clinical Associations, and Mechanisms

Review Article Emerging Comorbidities in Adult Asthma: Risks, Clinical Associations, and Mechanisms Hannu Kankaanranta,1,2 Paula Kauppi,3Leena E. Tuomisto,1and Pinja Ilmarinen1 1Department of Respiratory Medicine, Sein¨ ajoki Central Hospital, 60220 Sein¨ ajoki, Finland 2Department of Respiratory Medicine, University of Tampere, 33521 Tampere, Finland 3Department of Respiratory Medicine and Allergology, Skin and Allergy Hospital, Helsinki University Hospital and Helsinki University, 00029 Helsinki, Finland Correspondence should be addressed to Hannu Kankaanranta; [email protected] Received 11 September 2015; Revised 1 December 2015; Accepted 2 December 2015 Academic Editor: Anshu Agrawal Copyright © 2016 Hannu Kankaanranta et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Asthma is a heterogeneous disease with many phenotypes, and age at disease onset is an important factor in separating the phenotypes. Most studies with asthma have been performed in patients being otherwise healthy. However, in real life, comorbid diseases are very common in adult patients. We review here the emerging comorbid conditions to asthma such as obesity, metabolic syndrome, diabetes mellitus type 2 (DM2), and cardiac and psychiatric diseases. Their role as risk factors for incident asthma and whether they affect clinical asthma are evaluated. Obesity, independently or as a part of metabolic syndrome, DM2, and depression are risk factors for incident asthma. In contrast, the effects of comorbidities on clinical asthma are less well-known and mostly studies are lacking. Cross-sectional studies in obese asthmatics suggest that they may have less well controlled asthma and worse lung function. However, no long-term clinical follow-up studies with these comorbidities and asthma were identified. These emerging comorbidities often occur in the same multimorbid adult patient and may have in common metabolic pathways and inflammatory or other alterations such as early life exposures, systemic inflammation, inflammasome, adipokines, hyperglycemia, hyperinsulinemia, lung mechanics, mitochondrial dysfunction, disturbed nitric oxide metabolism, and leukotrienes. 1. Introduction Asthma is a common chronic disorder affecting more than 300 million people all over the world with prevalence among adults varying between 0.2 and 21% [1]. Recently, the cluster studieshaverevealedthatasthmaisnotasinglediseasebut a heterogeneous syndrome manifesting with distinct phenotypes. Age at asthma onset has emerged as a critical factor in distinguishing between phenotypes [2–4]. Patients with early-onset (or childhood-onset) asthma are typically atopic with Th2-predominant inflammation, good responsiveness to glucocorticoids, and good prognosis [5]. In contrast, patients with adultor late-onset asthma are often nonatopic, are females, have less favourable prognosis, and are more likely to develop persistent airflow limitation [2–4, 6, 7]. Most of asthma is thought to start during childhood. However, this has recently been challenged by showing that, in United States, adult-onset asthma is the dominant phenotype in women from 40 years of age [8]. Adult-onset asthma and adult-onset phenotypes have been associated with factors such as female sex, obesity, occupational exposure, rhinitis, respiratory infections, smoking, stressful life events, and low level of lung function [2–4]. As recently reviewed in this journal [4] the mechanisms of adult-onset asthma may include several metabolic and inflammatory components that arecommontotheotherdiseasessuchasobesity,metabolic syndrome (MBO), diabetes mellitus type 2 (DM2), cardiovascular diseases (CVD), and psychiatric diseases. Most clinical trials with asthma have been performed in patients being otherwise healthy. However, in real life, comorbid diseases are very common, especially in adult and/ or aging patients. For example, in the US 35% of adult people Hindawi Publishing Corporation Mediators of Inflammation Volume 2016, Article ID 3690628, 23 pages http://dx.doi.org/10.1155/2016/3690628 2Mediators of Inflammation Asthma GERD Rhinitis Atopy/allergy Vocal cord dysfunction Smoking COPD Previously recognized comorbidities/factors Obesity asthma risk clinical asthma (i) Increases (ii) Complicates Metabolic syndrome asthma risk (?) Increases Diabetes mellitus asthma risk Increases Cardiovascular diseases females with adult-onset asthma High risk in Mental diseases asthma risk clinical asthma (i) Increase (ii) Complicate Figure 1: Emerging comorbidities in asthma. are obese [9]. In addition, it is rather a rule than exception that patients not only often present with one comorbid disease but also have several comorbidities, that is, suffering from multimorbidity [10–12]. In early-onset childhood asthma, food allergies, atopic eczema, and allergic rhinitis are common and wellcharacterized comorbidities [13–16]. Some other comorbid conditions such as gastroesophageal reflux have gained a lot of attention during the years [17–19]. The role of these comorbidities has been thoroughly reviewed elsewhere [13–20]. Chronic obstructive pulmonary disease (COPD) is usually affecting age groups of 40 years and older. Asthma and COPD share many clinical features both being chronic obstructive airway diseases but having variable degrees of reversibility of airway obstruction [21]. The coexistence of asthma and COPD or the recently characterised asthma-COPD overlap syndrome (ACOS) has been reviewed and characterized in treatment guidelines of both asthma and COPD, for example, in Global Initiative for Asthma (GINA) and Global Initiative for Chronic Obstructive Lund Disease (GOLD) reports and in some national guidelines [22–26]. Thus, COPD and ACOS will not be covered by the present review. In this review, we aim to give the reader an overview of the emerging comorbid conditions to asthma such as obesity, MBO, DM2, CVD, and psychiatric diseases (Figure 1). We focusonasthmainadultsandespeciallyonadult-onset asthma if evidence is available. We have five separate aims in this review if such data is available: (A) to characterize the epidemiological evidence how these comorbidities associate with asthma, (B) to describe the role of the comorbidity as a risk factor for incident asthma, (C) the possible role of asthma as a risk factor for the incident comorbidity, (D) the effect of the comorbidity on the clinical outcome of asthma, and (E) to describe the possible common mechanisms that may link asthma and the abovementioned comorbid conditions. 2. Epidemiologic Studies on Comorbidities in Asthma A Norwegian study on 1 239 533 subjects of 8–29 years old comprised altogether 37 060 asthma patients when asthma was defined as using filled prescriptions on asthma drugs [27]. This study showed higher-than-expected occurrence in all of the diseases studied (attention-deficit hyperactivity disorder (ADHD), epilepsy, migraine, mental illness, cardiovascular, autoimmune, gastroesophageal reflux disease (GERD), allergy, use of antibacterials, and use of antivirals), except diabetes, in patients with asthma. Fifty-nine percent of the asthmatics had one or more of these chronic diseases when the corresponding figure for general population was 18%. In 20–29-year-olds the greatest odds ratios for other diseases in asthmatics were for allergy (OR 4.8 for men, 4.1 for women), GERD (OR 3.2 in men, 3.5 in women), and ADHD (OR 2.3 in men, 2.5 in women). The study population was 8– 29 years old but still showed high prevalence of comorbidity. In a Canadian population-based study (Ontario, Canada; population, 12 million) the burden of asthma-associated comorbidity as measured in rates of hospitalisations, emergency department visits, and ambulatory care claims was evaluated [28]. Asthma comorbidity-associated ambulatory claims, emergency department visits, and hospitalisations were substantial and, in fact, their numbers were much greater than those due to asthma itself [28]. Interestingly, the health burden due to asthma comorbidity appeared substantial regardless of age, gender, socioeconomic status, or living in a rural or urban area [28]. Approximately half of the asthma comorbidity claims were for other respiratory conditions such as upper respiratory tract infection, pneumonia, or allergic rhinitis [28]. In a further study by Gershon and coworkers [29] using the same Ontario data, comorbidity was evaluated as indicated by use of health service in 14 disease categories. In patients with asthma, comorbidity was 46% (0–4 years old), 40% (5–17 years old), 47% (18–44 years old), 49% (45–64-years old), and 22% (65 yearsoldormore)higherthaninthosewithoutasthma[29]. In all age groups most of the 14 disease categories were more common in patients with asthma. The highest comorbidity (50% or more) was found for respiratory disease other than asthma, psychiatric disorders, metabolic and immunity disorders, and perinatal disorders (0–4 years old). Risk of respiratorydisease(otherthanasthma)wasapproximately double, and risk of psychiatric disorders and infectious diseases was approximately 33% to 51% higher in individuals with asthma as compared to those without asthma. In the oldest age group, physician claims were approximately twice more common for acute bronchitis and 60% higher for pneumonia in those with asthma as compared to nonasthmatics [29]. The results from Great Britain among incident cases of asthma from primary care were similar showing that patients with asthma (𝑛 = 7931) have more consultations in all major organs systems than their ageand gender-matched nonasthma controls [30]. The mean age of the patients with asthma in all of the abovementioned studies ranged between 30 and 32 years [28–30] suggesting that a considerable Mediators of Inflammation 3 proportion of the patients represented asthma beginning during childhood. Analysis of aged (>65) patients with asthma suggests that the incidence of comorbidities increases andmorecloselyresemblesthatofCOPD[30].Thus,itis likely that some comorbidity, such as allergy, may be linked to childhood-onset asthma via common genetic and environmental mechanisms. However, other comorbidities (obesity, diabetes, depression, and anxiety disorders) may be related to asthma symptoms (e.g., sleep disturbance contributing to psychiatric disorders and obesity) or its therapy, for example, glucocorticoids inducing systemic adverse effects [31], diabetes [32], or increased risk for pneumonia [33]. A German telephone interview study of 2,242 current asthmatics (1,429 women) of a total of 43,189 study individuals (18 years or older) evaluated the prevalence of eight different health conditions (diabetes mellitus, hypertension, coronary heart disease, chronic heart failure, stroke, cancer, osteoarthritis, and depression) in patients with asthma as compared with those not having current asthma [34]. All of these eight health conditions were more prevalent in patients with asthma. Almost every fifth of the patients with asthma (17.8%) had at least 3 chronic conditions whereas 8.0% of controlswithnocurrentasthmahadatleast3chronicconditions. Interestingly, multimorbidity (i.e., three or more chronic conditions) was associated with increased risk for unscheduled inpatient care (OR 3.4) and for unscheduled outpatient care (OR 2.3) [34]. An analysis of Finnish public sector employees [35] reported that asthma increased the risk of all-cause long-term (sickness absence or disability pension >90 days) work disability (HR 1.8) as compared to controls (no asthma). However, asthma and one chronic comorbid condition increased the risk for long-term all-cause work disability with HR 2.2 and asthma together with two or more chronic conditions increased the risk with HR 4.5 [35]. According to the study results asthma is a minor risk for long-term work disability but asthma with multiple comorbidities is a major risk. Aging increases morbidity and also multimorbidity in patients with asthma [12]. By no means, multimorbidity is not a unique feature of asthma but rather represents clustering of diseases to certain persons. In fact, out of the 40 conditions studied in large analysis in Scotland [10], there was no condition in which most people had that condition only [12]. Multimorbidity is generally associated with increased risk for mental health disorders [10, 11]. Further, socioeconomic deprivation is associated with multimorbidity suggesting clustering of social, economic, and health problems in certain individuals or in certain areas. Taken together, comorbidity is commoninasthma;allergyandobesityarecommoninyounger age groups, whereas obesity, diabetes, GERD, and psychiatric and cardiovascular diseases are found in older age groups. Respiratory infections are found in all age groups. 3. Obesity 3.1. Is Obesity Associated with Asthma? Does Obesity Increase the Risk of Asthma? The studies evaluating the association between obesity and asthma use generally body mass index (BMI) as a tool. A BMI ≥25 is considered overweight, while people with BMI ≥30 are classified as obese. BMI is particularlyusefulasitisstandardized,calculatedinthesamewayfor both sexes and for adults of all ages [36]. Obesity is a risk factor for asthma, especially among women [37, 38]. A meta-analysis has been performed on the risk [17]. The risk for asthma was 1.20 for overweight and 1.43 for obese men. The corresponding risk estimates for women were 1.25 for overweight and 1.78 for obesity [17]. Also recent large US and Norwegian epidemiological studies report odds ratios ranging from 1.29 [39] to 1.84 [40] for obese males and 1.55 [39] to 1.96 [40] for obese females to have or to develop asthma as compared with their normal weight counterparts. What does this mean in real life? A 25-year follow-up in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort gives us an approximation. Approximately 1 out of 4 obese women followed up from the age of 25 developed asthma during the 25-year follow-up period, whereas approximately 1 out of 7 normal weight women developed asthma [41]. Does increasing obesity increase the risk of asthma? A recent large US epidemiological survey reported an association with the self-reported doctor-diagnosed asthma and the class of obesity. In class I (BMI 30–34.9) obesity OR for asthma was 1.27, in class II (BMI 35–39.9) obesity OR was 1.55, and in class III (BMI ≥40) OR was 1.85 indicating a positive association between the degree of obesity and asthma [39]. Similarly, a large Norwegian cohort [40] reported an increased odds ratio for asthma with increasing BMI (per 5 kg/m2) in females (OR 1.32) and in males (OR 1.38). In the US based survey [39] a sex difference was reported by showing that class III obesity is significantly more strongly associated with asthma in women (OR 2.11) than in men (OR 1.40). Similarly, a much less pronounced risk for the development of asthma was seen between normal weight and obese men in the CARDIA study [41]. However, the effect of obesity on the development of asthma may depend on the asthma phenotype. In the long-term follow-up of children hospitalised because of bronchiolitis and many subsequently developing asthma, obesity did not affect the development of asthma in this small cohort [42]. Although cross-sectional studies or follow-up of certain cohorts in adults has demonstrated an increased prevalence of asthma in obese individuals, many of these studies rely on self-reported weight and height. Another possible limitation of these studies is that most rely on a self-reported diagnosis of asthma or symptom-based assessment of asthma rather than on physician records, physiologic evaluation, or response to inhaled therapy. This raises the possibility that the respiratory symptoms are related to the physiologic impairment from obesity rather than to asthma [43]. This is especially important with regard to obesity as obesity increases the possibility to misdiagnosis of asthma [44, 45]. For example, obese subjects who make urgent visits for respiratory symptoms are more likely to receive a misdiagnosis of asthma [44]. Taken together, it appears that obesity is a risk factor for asthma. In contrast, the role of asthma as a risk factor for obesity is much less well-known. 4Mediators of Inflammation 3.2. Obesity and Clinical Asthma. To evaluate the clinical association between asthma and obesity we evaluated studies that directly compared asthma-related endpoints in a crosssectional or longitudinal study between patients (𝑛≥50) being normal weight or obese and reporting at least one objective measure of lung function. We identified 7 such studies [44, 46–51] together having 2597 patients with asthma (Table 1(a)). Even though most of these studies suffer from a small number of patients and exclude patients with other comorbidities, they give us an idea what the effect of obesity on asthma may be. All studies were cross-sectional and mostly included all severities of asthma. Most studies excluded smokers and patients with other comorbid states (Table 1(a)). Patients were adults (mean age between 32 and 57),buttheageattheonsetofthediseasewasnotreported. However, in five studies one can assume that the population contained both patients with childhoodand adult-onset asthma (Table 1(a)). The large analysis of the Severe Asthma Research Program (SARP) [47] evaluated the effect of obesity on asthma parameters separately in early-onset (<12 years) and late-onset (≥12 years) asthma. The results are not consistent across the studies (Table 1(b)). However, the results of these studies suggest that obese patients with asthma are older (Table 1(b)). They possibly present with higher age at onset and lower control of asthma, use more steroid courses, experience more hospital admissions and emergence department visits, and have lower lung function although these differences were not reported in all of these studies. Three studies [47–49] primarily recruited patients with severe asthma. The results of these studies are more consistent with regard to oral steroid use during previous year, lung function, and blood eosinophils (Table 1(b)). In support of obese patients presenting with more severe asthma, the association of body mass index and asthma severity was evaluated in the National Asthma Survey in the US [52]. In this large (𝑛 = 3095) telephone survey obese asthmatics were reported to present with symptoms all the time over the past 30 days (OR 1.7), to have greater than 2 missed work days in the past 12 months (OR 1.4), to use inhaled corticosteroid (OR 1.3), to have GINA medication step 2+ asthma (OR 1.4), to present with classes II–IV persistent asthma (OR 1.4), and to present with severe persistent (class IV) asthma (OR 1.4) [52]. In this cohort, 24% (i.e., almost every fourth) of normal weight patients were classified to have moderate to severe asthma, whereas the corresponding figure among obese patients was 35% [52]. These studies (Tables 1(a) and 1(b)) suggest that there are no differences in inflammatory markers such as blood eosinophils (four studies, 𝑛 = 1905), FENO (three studies), high-resolution computerized tomography scan (one study), and sputum inflammatory cell profiles (one study). In addition, these studies suggest that other comorbidities such as GERD, diabetes mellitus, hypertension, and obstructive sleep apnoea syndrome may be more common in obese asthma patients, although comorbidities were mostly not analyzed (Table 1(b)). Interestingly, two studies [47, 51] reported a reduced probability or tendency of being allergic when being obese and having asthma. This is in agreement with the results obtained from cluster studies that suggest that the recently identified group of patients with adult-onset obese noneosinophilic asthma phenotype are less allergic/atopic [2–4]. Further, the SARP study found that the effect of obesity is different and more pronounced in early-onset asthma than in late-onsetasthma[47].Thus,asthmabeginninginchildhood, when being persistent, might be significantly complicated by obesity developing later in life whereas asthma beginning later in adulthood (possibly to the already obese patient) may not be so much more complicated by obesity as obesity may already have been a major driving factor in its appearance. In future, it is of utmost importance to differentiate between patients having asthma and becoming obese later and obese patients with new-onset asthma. In a small Canadian study [46] (Tables 1(a) and 1(b)), the group of obese asthmatics presented with lower asthma controlandhadreducedtotallungcapacity(TLC),expiratory reserve volume (ERV), functional residual capacity (FRC), andresidualvolume(RV)comparedtothenormalweight asthmatics [46]. It is well-known that obesity is associated with a reduction in ERV and FRC [53–55], but it still remains contradictory, whether obesity or BMI as such is associated with more severe airway obstruction (FEV1/FVC) (see Tables 1(a) and 1(b)). How existing obesity affects the therapy, control, and prognosis of asthma in a prospective setting? We identified one 12-month prospective disease management study that evaluated the impact of obesity in asthma [43]. In children, therewasnorelationshipbetweenBMIandseverityof asthma, spirometry findings, quality of life (QoL), or healthcare utilization. In adults, there was no relationship between BMI and asthma severity or health care utilization but higher BMI was associated with a significant reduction in QoL and the BMI had an inverse relationship with forced vital capacity (FVC) [43]. The association of obesity with asthma control has been analysed in a large asthma population (Kaiser Permanente Southern California) (𝑛=10,233) [56]. Overweight and obesity were associated with increased relative risk for asthma hospitalizations or emergency department visits (RR 1.4). Obesity was associated with an increased risk for dispensing ≥7 short-acting beta-agonist canisters [56]. These analyses suggest that obesity may have different impact on asthma in younger age groups than in adults and that obesity is associated with more asthma symptoms, reduced TLC, and poorer asthma control. 3.3. The Effect of Weight Loss on Asthma and the Effect of Obesity on Pharmacotherapy. Does weight loss improve asthma control? A randomized study by Stenius-Aarniala and coworkers [57] showed that weight loss in 38 obese physiciandiagnosed asthmatics is associated with improvements in asthma symptoms, lung function, and health status. This has been confirmed in another study [58] showing that dietary restriction,withorwithoutexerciseresultedinagreaterbenefit in terms of asthma control. Recently, a small controlled study (𝑛=16+6) reported that significant weight loss (from 115 kg →98 kg/BMI 45 →36.5) was associated with a significant improvement in PC20 (5 →10 mg/mL), FVC% predicted (94 →100), asthma control (ACQ score 1.4 →0.6), Mediators of Inflammation 5 Table 1: (a) Background information of clinical studies evaluating the effect of obesity on asthma in adults. (b) Results of clinical studies evaluating the effect of obesity on asthma in adults. (a) Study Patient with asthma 𝑛Setting Country Asthma criteria Severity levels included Smokers included Other exclusion criteria Onset of asthma (child/mixed/ adult) Gender (Females%) Age (mean; years) Lessard et al., 2008 [46] 88 Crosssectional Canada Confirmeddiagnosisbasedon bronchodilator response or airway responsiveness measurements All No Current smoking or ex-smoker for ≤6mo Mixed 68–100 32–44 Pakhale et al., 2010 [44] 346 Crosssectional Canada Sequential lung testing All Yes (?) Asthma ruled out using sequential testing Mixed 66–73 41–47 Holguin et al., 2011 (SARP early-onset) [47] 543 Crosssectional US A 12% increase in FEV1after a short-actingbronchodilator or a 20% decrease in FEV1 after inhalation of methacholine (PC20, 25 mg/mL) All No Current smoking or smoking history of 5 years or more Childhoodonset (<12 years) 49–65 26–35 Holguin et al., 2011 (SARP late-onset) [47] 506 Crosssectional US All No Late-onset (12 years or more) 65–74 39–45 Gibeon et al., 2013 [48] 666 Crosssectional UK ATS definition of refractory asthma Severe Yes (?) NR Mixed 65 45 Bruno et al. 2014 [49] 102 Crosssectional Italy/France ATS 1987 Severe No Potential confounding diagnosis. Any persistent environmental trigger, COPD, or other differential diagnoses Mixed 56 57 Ramasamy et al., 2014 [50] 60 Crosssectional India GINA 2009 All No Smoker (current or ex), ICS/OCS during previous month, medication for obesity, hypertension, diabetes mellitus/CAD, unable to perform exhaled nitric oxide maneuver Mixed 50 32–35 (inclusion 20–50 years) Ciprandi et al., 2014 [51] 286 Crosssectional Italy Documented asthma diagnosis by a specialist based on a history of intermittent wheezing in combination with reversibility to bronchodilators and/or BHR to methacholine All No (?) Historyoflungdisease other than asthma, coronary artery disease, congestive heart failure, cor pulmonale, recent asthma exacerbation or presence of acute (in the last 4 weeks) or chronic upper and/or lower respiratory infections NR 59 48 NR = not reported, FEV1= forced expiratory volume in 1 second, ATS = American Thoracic Society, SARP = the Severe Asthma Research Network, BHR = bronchial hyperresponsiveness, ICS = inhaled corticosteroid, OCS = oral corticosteroid, and CAD = coronary artery disease. 6Mediators of Inflammation (b) Age Age at onset Asthma duration Asthma control Exacerbations last year Oral steroids for asthma in the previous year Hospital admissions last year Urgent visits to health care due to respiratory symptoms or ED visit preceding year Hospitalization for asthma ever Intensivecareunit for asthma ever or previous year Other Lessard et al., 2008 [46] ↔ND ↔↓ND ND ND ND ND ND TLC, ERV, FRC, and RV lower in obese asthmatics Pakhale et al., 2010 [44] ↑↑ ↔ND ND ND ↔↔ ND ND Obese individuals who make urgent visits for respiratory symptomsaremorelikelyto receive a misdiagnosis of asthma Holguin et al., 2011, early-onset [47] ↑↔↑ND ND ↑↑ ↑ ND ↑Asthmatic subjects are differentially affected by obesity based on whether they had asthma early (<12 years of age) or later in life Holguin et al., 2011, late-onset [47] ↑↑ ↔ND ND ↔(↑)↑ND ↑ Gibeon et al., 2013 [48] ↔↔ ↔ ND ND ↑↔↔ ND ↔No difference in FENO or sputum eosinophils Bruno et al., 2014 [49] ↔ND ↔↓(↑)↑ND ND ↔↔BMI represents per se a factor for the deterioration in disease control in severe asthma Ramasamy et al., 2014 [50] (↑)ND ↔ND ND ND ND ND ND ND No difference in FENO and hsCRP Ciprandi et al., 2014 [51] ↑ND ND ↔ND ND ND ND ND ND No difference in FENO FEV1 (% pred.) FVC (% pred.) FEV1/FVC LABA use Blood eosinophils Total IgE Allergic sensitization GERD Diabetes mellitus Hypertension Obstructive sleep apnea syndrome Anxiety/depression Lessard et al., 2008 [46] ↔↔ ↔ ND ↔↔↔ ND ND ND ND ND Pakhale et al., 2010 [44] ↓ND ND ND ND ND ND ↑↑↑ ND ND Holguin et al., 2011, early-onset [47] ↓↓ ↓ ↑ ↔↔↔ ND ND ND ND ND Holguin et al., 2011, late-onset [47] ↓↓ ↔↑↔↔ (↓)ND ND ND ND ND Gibeon et al., 2013 [48] ↔↓↔ND ↔↓(↓)↑ND ND ND ND Bruno et al., 2014 [49] (↓)(↓)↔↑↔↔↔ ↔ ↑↔↑↔ Ramasamy et al., 2014 [50] ↔↔ ↔ ND ND ND ↔ND ND ND ND ND Ciprandi et al., 2014 [51] ↓↓ ↓ ND ND ND ↓ND ND ND ND ND ND = not defined; FEV1=forcedexpiratoryvolumein1second.FVC=forcedvitalcapacity.LABA=long-acting2-agonist.GERD=gastroesophagealrefluxdisease,TLC=totallung capacity, ERV = expiratory reserve volume, FRC = functional residual capacity, RV = residual volume, FENO = forced exhaled nitric oxide, hsCRP = high sensitivity C-reactive protein, and ED = emergency department. Mediators of Inflammation 7 and asthma quality of life (AQLQ score 5.6 →6.1) [59]. In addition, small studies [60–62] have suggested that surgically induced weight reduction is associated with benefits in asthma control, symptoms, hyperreactivity, use of medication, and lung function. Markers of systemic inflammation (hsCRP, adiponectin, and leptin) were reported to be lower after bariatric surgery, whereas only a decrease in mast cells was reported in a group of asthmatics undergoing bariatric surgery [61]. However, the published studies are small (actively treated asthma patients together 27+23+12) [60–62] and the results suggest that the benefit may diminish over time [60]. Another factor that makes it difficult to assess the effect of weight loss interventions on asthma is that bariatric surgery improves lung function (e.g., FEV1,FRC, andTLC)inobesepatientswithoutasthma[61],suggesting that all improvement is not specific to asthma. A recent self-controlled case series study [63] of obese patients with asthma (𝑛 = 2261) and undergoing bariatric surgery gives hope that weight loss and bariatric surgery are associated with clear benefits in asthma. Significantly fewer emergency department (ED) visits or hospitalizations for asthma exacerbationsoccurredwithin12monthsafterbariatricsurgery (11% of patients) compared to during the reference period (22% of patients) and the risk remained low in the subsequent period of 13 to 24 months after bariatric surgery (11% of patients) [63]. In practical terms this means that before bariatric surgery 22 patients out of 100 experienced ED visit or hospitalization and after surgery only 11 out of 100 experience such adverse event because of asthma. Obesity may also affect the response to the pharmacotherapy of asthma. The basic choices of pharmacotherapy [22, 31] of asthma as such are valid also in obese asthmatics. However, the obese asthmatics may be less responsive to standard asthma therapy with ICS as compared with normal weight patients [38] even though the findings are not consistent. 4. Metabolic Syndrome and Asthma Obesity (high waist circumference) is a major component of metabolic syndrome, a cluster of metabolic components that indicate a significantly increased risk of cardiovascular disease [64]. The other components of metabolic syndrome include elevated triglycerides, reduced high-density lipoprotein (HDL) cholesterol, high blood pressure, and elevated glucose or diabetes. In contrast, the association of metabolic syndrome as a syndrome (i.e., not its single components) with asthma has been much less studied [64]. The Norwegian prospective cohort of the Nord-Trondelag Health Study from 1995 to 2008 [65] reported that metabolic syndrome was a risk factor for incident asthma (OR 1.6). Among components of metabolic syndrome, two remained associated with incident asthma: high waist circumference (OR 1.6) and elevated glucose or diabetes (OR 1.4) [65]. In the CARDIA study abdominal adiposity, elevated blood pressure, and impaired fasting glucose or diabetes were significantly associated with incident asthma. However, after adjustment for BMI their significance was lost suggesting that BMI as such is an independent risk factor for asthma in women [41]. In Korean 40–69-year-old adults, symptoms suggestive of asthma such as wheezing, resting dyspnea, and postexercise dyspnea were increased in the subjects of the metabolic syndrome group [66]. Abdominal obesity and hypertension were the risk factors for asthma-like symptoms among the components of the metabolic syndrome [66]. The association between obesity and asthma has been already largely studied (see above sections) and the association between DM2 and asthma will be dealt with separately in Section 5. Next, we will shortly review the associations between lipid metabolism and hypertension with asthma. The complex cholesterol and lipoprotein biology [67, 68] are outside the scope of the present review and the oversimplistic “good and bad cholesterol” view does not represent the whole phenomenon. Although several experimental animal studies as well as some epidemiological and clinical studies in children and adolescents [67, 68] suggest an association between cholesterol/lipoproteins and asthma, surprisingly few studies have been published on adults with asthma. Two early studies [69, 70] report conflicting findings in comparing the cholesterol/lipoprotein profiles in adult patients with asthma and healthy controls. A very recent study [71] evaluated the levels of apolipoprotein A-I and large high-density lipoprotein in adult atopic asthma. Serum levels of these positively correlated with FEV1, whereas serum triglycerides, LDL cholesterol, and apoB were associated with more severe airflow obstruction [71]. Even though the correlations were weakandonlyatopicasthmaticswereincluded(possibly excluding a larger part of the nonatopic adult-onset asthma population) in this cross-sectional study, it raises an interesting possibility. It suggests that the atherogenic lipid profile is associated with reduced FEV1in asthma [68] creating an important link between metabolic syndrome and asthma. Data from Canadian Community Health Survey with self-reported or self-reported doctor-diagnosed conditions has shown in two different studies that patients with asthma were having approximately 1.4-fold risk for high blood pressure [72, 73]. Similarly, in a sample of Jackson Heart Study, use of medication for hypertension was more common among those African American women reporting current doctordiagnosed asthma or use of medication to treat asthma [74]. Taking medication for hypertension was a significant risk factor for current asthma in this population [74]. A similarfindinghasbeenreportedamongArabAmericans [75]. Taken together, there is evidence from the epidemiological studies that hypertension and asthma are connected. However, there is scarcity of data from clinical studies whether hypertension complicates asthma or vice versa. A recent study using Kaiser Permanente Southern California registry data showed that hypertension is associated with markers of increased severity of asthma such as use of >6 canisters of short-acting 𝛽2-agonist in a 12-month period, oral corticosteroid dispensing, and history of emergency department visits or hospitalizations [76]. Taken together, it still remains unclear whether metabolic syndrome itself is a risk factor for asthma or is the risk factor one (or several) of its components (obesity?). In addition, the impact of MBO or its therapy on clinical asthma remains mostly unknown [64]. 8Mediators of Inflammation 5. Diabetes Mellitus and Asthma Type I diabetes has been suggested to be an autoimmune disease due to environmental factors, possibly viruses, whereas type 2 diabetes mellitus has been connected with obesity, insulin resistance, and systemic inflammation [77–80]. An analysis of the large Kaiser Permanente Medical Care program has evaluated the risk of asthma among those with diabetes. In adults (aged ≥18 years) with no diabetes ageand sex-adjusted incidence of asthma was 0.16 per 1,000 personyears and in those with diabetes the corresponding figure was 0.41 indicating a higher risk for incident asthma [78]. This association between increased prevalence of asthma in patients with DM2 has also been confirmed in a large Danish twin study [79] and in hospitalized patients [80]. The proposed mechanisms how asthma could increase the risk for DM2 include genetic pleiotropy, lung-related inflammatory cytokines and their effects on insulin sensitivity, direct effects of hypoxia on glucose metabolism, and adverse early-life exposures and their effects on organ development [81]. In addition, severe asthma is treated with repeated courses or persistent per oral glucocorticoids that may increase the risk of type 2 diabetes [32] even though this has not been confirmed in other studies [82, 83]. Risk estimates for diabetes in patients with asthma have varied from 1.3 to 2.1 [81, 84, 85]. Asthma-diabetes association appeared stronger for adultversus child-diagnosed asthma cases, and for participants who were obese compared to those who were nonobese [81]. The current data suggests that a connection between asthma and DM2 diabetes exists and suggests that both diseases are able to increase the risk of the other disease. In contrast, the effectofDM2onasthmaoutcomeremainsunknown. 6. Cardiovascular Diseases and Asthma Previously connection of asthma and arteriosclerosis has been evaluated in studies of asthma mortality or in studies among elderly patients with asthma. Patients with severe asthma have been reported to have a higher mortality from ischemic heart disease especially among women [86]. However, such a connection between these diseases has not been found in elderly asthma patients [69, 87]. 6.1. Are Asthma and Cardiovascular Diseases Associated? A large cross-sectional study (𝑛=16,943)lookedfortheassociations between adult-onset asthma and CVDs including stroke, congestive heart failure, and coronary heart disease [88]. Adult-onset asthma (age of onset ≥18 years) was found to have a significant association with total CVD (OR 2.1). Only coronary heart disease (CHD) was significantly associated with adult-onset asthma (OR 2.3). In gender stratified analyses, only females with adult-onset asthma showed an increase in the odds for total CVD (OR 2.4) and CHD (OR 2.9). In contrast to expectations, overweight (BMI 25–30) females with adult-onset asthma had stronger association with CVD than those having adult-onset asthma and being obese (BMI >30) [88]. The limitations of the study were the cross-sectional setting and definition of smoking history (nonsmokers or current smokers) thus making exclusion of COPD impossible [88]. 6.2. Does Asthma Increase the Risk of Cardiovascular Diseases? Overthepastdecadelargecohortstudieshavebeenpublished to assess the risk of cardiovascular events as asthma comorbidities. In a large cohort study of health insurance database (𝑛 = 151,620) connection of asthma and combined nonfatal or fatal CHD was assessed [89]. Patients (age ≥18 years) with self-reported physician-diagnosed asthma or hospitalization duetoasthmawerefollowedfor27years.Inwomen,the age-adjusted CHD rate was higher in those with asthma than in those without asthma with a HR of 1.2. Asthma was associated with the risk of developing CHD in both younger (<50 years) (HR 1.2) and older (≥50 years) women (HR 1.2). Asthma among women became significantly associated with CHD events already after 10 years of follow-up (HR 1.2). This suggests that women might have a greater biological susceptibility to the inflammatory asthma milieu or to the cardiotoxic or metabolic effects of asthma medications [89]. Several studies of the Arteriosclerosis Risk in Communities (ARIC) cohort have been published concerning asthma and CVDs as comorbidity [90]. In a prospective study with 14 years of follow-up asthma was modestly associated with an increased incidence of stroke [91]. In a further study of thesamecohort[92]evaluatingtherelationshipbetween asthma and carotid artery intima-media thickness (IMT) also the age at asthma onset was taken into consideration [92]. The weighted mean for wall IMT thickness for women with history of adult-onset asthma (≥21 years) was significantly greater than that of women without asthma. In contrast, IMT in women with a history of childhood-onset (<21 years) asthma did not differ substantially from nonasthmatic women. Third study of the ARIC cohort [93] evaluated incidence of CHD and stroke among asthma subtypes (asthma onset <or ≥21 years). Women, but not men, with adult-onset asthma were found to have a 2-fold increased rate of CHD compared to their nonasthmatic counterparts. Iribarren and coworkers [94] followed two matched adult cohorts, the other with asthma and a parallel asthma-free cohort. Both cohorts were followed up for 12 years for incident nonfatal or fatal CVD and all-cause mortality. Asthma was associated with a 1.4-fold increased risk of coronary heart disease, a 1.2-fold risk of cerebrovascular disease, a 2.1-fold risk of heart failure, and a 3.3-fold risk for all-cause mortality. SimilarlytothatfoundintheARICcohort[92,93]stronger associations were noted among women, but there was no data on asthma onset or asthma severity [94]. Among patients with asthma, 84% used one or more asthma medication and particularly those using oral corticosteroids alone or in any combination with asthma medications were at enhanced riskfordevelopingCVD,whichmayreflectthatthatthey were having severe asthma [94]. There remains a possibility that the medication used may increase the risk of CVD as especially 𝛽2agonists have many adverse cardiovascular sideeffects and continuous use of glucocorticoids may have many metabolic disadvantages [89, 94]. Recently, a long-term (10 years) prospective study reported an association of persistent asthma and CVD events (coronary death, myocardial infarction, angina, stroke, and CVDdeath)[95].Allparticipants(𝑛 = 6792)werefreeof CVD at baseline. Self-reported asthma cases (𝑛 = 667)were Mediators of Inflammation 9 classified as persistent (daily use of controller medication such as ICS, LTRA, and OS) in 77% and intermittent (without controller medication) in 23% of patients. After a decade of follow-up patients with persistent asthma had a 1.6–1.7-fold higher risk of CVD events than nonasthmatics. In addition, markers of systemic inflammation (IL-6, CRP, alfa-dimer, and fibrinogen) were the highest in patients with permanent asthma even though patients were using modern controller asthma medication. Use of controller medication did not abolish the increased risk of CVD events [95]. Current and former smoking are one of the main risk factors for both asthma and cardiovascular diseases. Recently published report [96] from the Copenhagen General Population study cohort (𝑛=94,079) assessed prospectively the risk of asthma and CVD including ischemic heart disease, myocardial infarction, and ischemic stroke among smokers and nonsmokers. Six percent (𝑛 = 5691) had self-reported asthma, 40% were never smokers, 43% former smokers, and 16% current smokers. Mean follow-up time of the study patients (age 20–100 years) was 4.5 years. Hazard ratios among individuals with asthma compared to never smokers without asthma for ischemic heart disease were 1.5 in former smokers and 2.0 in current smokers. The respective corresponding values were 1.7 and 3.2 for myocardial infarction and 1.2 (n.s.) and 3.0 for ischemic stroke. In contrast to previous studies the increased risk for cardiovascular comorbidities in this cohort study was restricted only to smokers with asthma [96]. Unfortunately data on the age at asthma onset was not available as in other cohorts the increased risk of CVD was seen mostly only in women with adult-onset asthma.Inaddition,thefollow-uptime(4.5years)isrelatively short for the never smoker asthma group as they were women withameanageof53.Theriskofmyocardialinfarctionin smoking persons increases more early but in never smokers (especially women) it clearly increases only after the age of 60 [97]. In most asthma comorbidity studies confounding effect of smoking has been taken into account. Usually patients have been divided into groups of current, ever, and never smokers. Insomestudiesdataonpack-yearsisavailable.However, more detailed information like duration, intensity, and type of smoking as well as age of smoking onset and second hand smoking should be part of the multivariate models especially in studies concerning asthma and the risk of cardiovascular diseases [98]. These cross-sectional and cohort studies with large populations have shown that asthma patients and especially a subgroup of adult-onset asthma women are at increased risk of arteriosclerosis. In future, it would be important to know whether totally controlled asthma would reduce the risk of cardiovascular comorbidities. The role of contemporary asthma medication to prevent or to enhance incidence of cardiovascular diseases also remains obscure. Furthermore, we lack knowledge of how different CVDs affect asthma outcome and whether CVDs are of importance in making decisions on how to modify treatment of asthma. 7. Mental Disorders, Suicide, and Asthma The association between asthma and psychological factors has been recognized for centuries [99]. Psychosocial factors have long been suspected to influence the onset and course of asthma. These effects may be mediated via direct influences such as influences on the pulmonary system, autonomic and endocrine regulation, and inflammatory and immune process (see later in this paper and [100]). In addition, psychosocial factors can influence asthma via multiple indirect pathways such as medication adherence, perception of airway obstruction (either overperception or underperception), illness beliefs, or general health behavior [100]. A considerable number of studies have suggested that there is an association between some mental disorders and asthma,especiallysevereasthma[99–101].Studiesconducted among clinical and general practice samples have found higher than expected rates of anxiety disorders (particularly panic disorder) and of depression among adult patients with asthma[99].However,thepublishedresultshavenotalways been consistent and methodological problems (e.g., not using DSM-based diagnostics and variability in the assessment of asthma) make it difficult to draw clear conclusions [99, 100]. 7.1. Is There Association between Asthma and Mental Disorders? TheWorldMentalHealthSurveyperformedin17 countries (𝑛=85,088) using general population sample reports that an adult with asthma has an increased risk for depressive disorders (OR 1.6) and anxiety disorder (OR 1.5) as compared with persons not having asthma [101]. A metaanalysis estimating the prevalence of anxiety disorders in asthma reported that the average prevalence of any anxiety disorder among adults with asthma was 34% [102]. More specifically, the prevalence of panic attacks (25%), panic disorder (12%), agoraphobia (12%), and generalized anxiety disorder (9%) was higher among adults with asthma than in the general population [102]. A recent meta-analysis has evaluated the association between asthma and depression [103]. Patients with depression had increased risk for having asthma (OR 3.2) as compared with those not having depression and patients with asthma had an increased risk for having depression (OR 1.5) as compared with those not having asthma [103]. A similar association has been reported from SpanishNationalHealthSurvey[104]reportingthatasthmatic patients suffer more often from anxiety (9.7%) and depression (9%) than persons not having asthma (6.6% and 5.5% for anxiety and depression, resp.). Having asthma increased the probability of suffering from anxiety (OR 1.3) and depression (OR 1.4). Among asthmatics factors associated with suffering from anxiety were older age, concomitant comorbidities, and visits to GP practices in the last 4 weeks, whereas factors associated with depression were female sex, older age, worse self-related health, concomitant comorbidities, abstemious individuals, and the need for attendance on emergency room in the last year [104]. A similar association has been reported also from Germany reporting that lifetime severe asthma was significantly associated with an increased risk for a number of anxiety disorders (any anxiety disorder, panic disorder, panic attacks, social phobia, specific phobia, and generalized anxiety disorder), bipolar disorder, and any severe mental disorder [105]. Lifetime nonsevere asthma was significantly associated with having any anxiety disorder, not specified anxiety disorder, and with any somatoform disorder [105]. 16 Mediators of Inflammation of asthma. That kind of study would require a different experimental setting. For example, measurement of certain mediators in large population samples and following whether these people later develop incident asthma or not might help to resolve those questions. For comorbidities such as MBO or its components, DM2 and CVD, we lack studies that evaluate their effect on clinical asthma. There exists some preliminary evidence on the deleterious effects of obesity and mental disorders on asthma outcome (Figure 1). Clinical studies that evaluate long-term prognosis and the contribution of obesity (or other comorbidities) on asthma are needed. In addition, studies that evaluate changes in the comorbidity over time on asthma control, exacerbations, lung function, and drug usage are lacking. Obesity has been in focus during last years. However, obesity itself is associated with significant comorbidity (such as diabetes, cardiovascular diseases, and mental diseases) and lifestyle factors (such as smoking, unhealthy diet, chronic alcohol use, and low level of physical exercise) that may contribute to the asthma outcome. From the mechanistic point of view it may be rational to include patients with only single comorbidity (e.g., obesity) to asthma studies at the time (see, e.g., Table 1(a)). However, from the perspective of practicing respiratory specialist or general physician this is not optimal as most patients suffer from multimorbidity rather than from a single disease or a combination of two specific single diseases. For example, in Germany most patients (approximately 60%) have one or more diseases out of eight listed in addition to asthma [34]. In Scotland with a sample of almost 1.8 million people of all ages, multimorbidity affects one in four people [10]. Multimorbidity is often met in chronic diseases and in the elderly population [12]. Studies in patients with asthma that do not exclude patients because of comorbidities are thus warranted. Studies such as the Sein¨ ajoki Adult Asthma Study (SAAS) that evaluate the longterm prognosis of new-onset asthma diagnosed at adult age and excludes only childhood-onset patients may shed light on this matter [219]. Many of the comorbidities associated with asthma occur as cluster of diseases rather than as a single combination of asthma with a specific comorbidity. As many of the suggested mediators are common to these diseases, we propose that there may not be a single mechanism for interaction between asthma and certain comorbidity and another separate mechanism for the interaction between asthma and second comorbidity, and so forth. Instead, we think that there exists a group of mechanisms that link with each other and most link with obesity and/or components of metabolic syndrome. 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