Asthma and comorbidities

Ledford, Dennis K.; Lockey, Richard F.

Current Opinion in Allergy & Clinical Immunology:
doi: 10.1097/ACI.0b013e32835c16b6
MECHANISMS OF ALLERGY AND ADULT ASTHMA: Edited by Stephen T. Holgate and J. Andrew Grant

Purpose of review: This article summarizes the more common comorbidities which, in the opinion of the authors and supported by the medical literature, frequently affect asthma management. Optimal asthma control requires accurate diagnosis, implementation of effective therapy, and evaluation of coexisting conditions. Comorbidities refer to either coexisting conditions or interacting conditions, with the latter having a more significant influence on the management of asthma. This review provides the authors’ clinical perspective of the more common comorbidities and relevant literature reviewed primarily from the past 4–5 years.

Recent findings: Optimizing rhinitis and rhinosinusitis management and addressing allergic sensitivity and allergen exposure are achievable measures for the most common asthma comorbidity. Psychological dysfunction and paradoxical vocal cord dysfunction are frequently associated with poor asthma control. The effects of obesity are inconsistent in the literature but obesity likely affects asthma symptoms and possibly its pathogenesis. Treatment of asymptomatic gastroesophageal reflux does not improve asthma.

Summary: Asthma is a common disease and other conditions frequently occur concomitantly in individuals with asthma. Asthma is usually very treatable and comorbidities should be considered and addressed or the asthma diagnosis questioned if treatment effects are not optimal. Evidence-based medicine is lacking as most asthma studies exclude comorbidities; additional studies are needed.

Author Information

aMabel and Ellsworth Simmons Professor of Allergy and Immunology, Professor of Medicine and Pediatrics

bDivision of Allergy and Immunology, Joy McCann Culverhouse Airways Disease Research Center, University of South Florida Morsani College of Medicine

cJames A. Haley Veterans’ Administration Hospital, Tampa, Florida, USA

Correspondence to Dennis Ledford, James A. Haley V.A. Hospital, 13000 Bruce B. Downs Blvd, VAR 111D, Tampa, FL 33612, USA. Tel: +1 1 813 972 7631; e-mail:

Article Outline
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The term comorbidity is frequently misapplied if one accepts the preferred definition, that is, a coexistent disease or condition. In this context, comorbid conditions occur together but do not necessarily influence one another. In contrast, clinicians frequently use the term comorbidity to describe conditions that mutually affect the other, as such interactions complicate diagnosis, management, and assessment more than coincident diseases. Common diseases by coincidence will coexist with asthma due to the high prevalence of asthma, affecting approximately 8% of the adult population in the United States and up to 15% of children. In this article, the authors have taken the liberty of using asthma comorbidity when referring to a condition that influences asthma severity, management, or recognition or when referring to a disease affected by asthma. These relationships include increased severity of one or both diseases, an increased prevalence of one disease as a result of the other, a shared pathogenic process between the two, and misattribution of shared symptoms.

Asthma has a variable time of onset and clinical course. Comorbidities will vary with age and clinical context. Asthma control is based partially upon symptoms that are shared or influenced by many comorbid conditions. Misattribution of symptoms is a frequent influence of comorbidities on asthma assessment. For example, a condition such as gastroesophageal reflux disease (GERD), which is a comorbidity of asthma, may result in symptoms of cough and chest tightness without asthma. If both conditions are present, observed symptoms could result from worsening asthma independent of GERD, asthma could aggravate GERD and increase GERD symptoms, GERD could increase asthma symptoms or both conditions independently may result in similar complaints.

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The effectiveness of asthma treatment as summarized in a variety of guidelines makes asthma management generally satisfactory. However, surveys show in a variety of settings that achieving optimal asthma control varies from 30 to 70% [1▪,2]. Asthma is prone to exacerbations that result in an inherent unpredictability, which can be minimized but not eliminated. However, individuals who do not respond or respond inconsistently to treatment often have a comorbidity. These comorbidities may result in misdiagnosis, misinterpretation of symptoms, aggravation of one or both diseases, or decreased adherence [3▪▪,4]. Recognition of these comorbidities facilitates more appropriate therapy or reduction of potentially risky therapies, such as systemic corticosteroids.

Comorbidities increase the likelihood of poorly controlled asthma as evidenced by a relatively small study by ten Brinke et al.[5▪▪]. Individuals with a confirmed diagnosis of asthma and frequent exacerbations were surveyed for coexisting conditions. The association was calculated for a specific comorbidity and the likelihood of more frequent asthma exacerbations. One hundred and thirty-six individuals completed the survey. The odds ratio (OR) of experiencing an asthma exacerbation was increased 10.8-fold by depression, 4.9-fold by GERD, 3.7-fold by severe sinus disease, and 3.4-fold by obstructive sleep apnea.

Most of the data in the medical literature supporting a relationship of asthma with other comorbidities are based upon cross-sectional surveys or small cohorts. These data cannot confirm causal relationships or show the direction of any observed or suspected relationship. Thus, for the most part, the discussion in this article reviews possibilities rather than confirmed relationships.

The order of the comorbidities is based upon the authors’ experience and their opinion as to the relative frequency of occurrence as well as the available medical literature to support the association [3▪▪]. Numerous potential comorbidities with asthma will not be discussed in this review but are listed at the top of the next page. In addition, the clinician should consider alternative diagnoses when asthma control is elusive. Bronchial and pulmonary diseases likely to be confused with asthma are provided in Table 1. Diseases, conditions, or medications that result in shortness of breath or cough are listed below.

1. Anemia

2. Deconditioning

3. Heart disease

4. Medications (angiotensin converting enzyme inhibitor)

5. Pulmonary embolus

6. Pulmonary hypertension

7. Thyroid compression of trachea (retrosternal thyroid)

8. Vascular ring

9. Vasculitis

Comorbidities of asthma are listed below. Some of the comorbidities overlap, for example, allergic rhinitis and rhinitis and respiratory infection or ‘bronchitis and bronchopneumonia’. The list is based upon health administration data of approximately 12 million children and adults, 1.5 million of whom had asthma.

Comorbidities of asthma are as follows [6▪▪]:

1. Allergic rhinitis

2. Atherosclerotic cardiac disease and circulatory disorders

3. Bronchitis and bronchopneumonia

4. Connective tissue diseases

5. Dermatologic conditions (eczema)

6. Gastroesophageal reflux (GERD) and other gastrointestinal disease

7. Immunologic and hematologic diseases

8. Metabolic disorders

9. Neurologic disorders

10. Obesity

11. Obstructive lung disease (COPD)

12. Paradoxical vocal fold movement [vocal cord dysfunction (VCD)]

13. Pregnancy

14. Psychologic disease (anxiety, depression, behavioral disorders)

15. Respiratory infection

16. Rhinitis and rhinosinusitis

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Upper airway disease incorporates rhinitis, sinusitis, and rhinosinusitis, all of which are associated with postnasal drip. Allergic rhinitis is the most common form of rhinitis, affecting approximately 20% of adults and over 30% of children. Nonallergic rhinitis also affects a large number of people, usually adults more than children. The lack of specific diagnostic criteria for nonallergic rhinitis limits epidemiologic studies. Overlap of allergic and nonallergic rhinitis is also common and is termed mixed rhinitis by some authors. Sinusitis is more likely in individuals with rhinitis, and chronic sinusitis is coincident with nasal inflammation, leading to the term rhinosinusitis [7].

Upper airway symptoms also may result from anatomic issues related to the upper airway, such as adenoid hypertrophy and nasal septal deviation. In addition, symptoms may result from nasal polyposis, usually with rhinosinusitis. Polyposis is generally associated with nonallergic rhinitis, though not exclusively.

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Relationship with asthma

Asthma is almost always associated with nasal disease, in up to 95% of cases in some studies. This association is allergic rhinitis in individuals with allergic asthma and nonallergic rhinitis in nonallergic asthma [8]. Chronic rhinosinusitis is frequently linked to persistent, severe asthma, as is nasal polyposis [7,9,10]. Treatment of the upper airway disease improves asthma for a variety of reasons. Ideal management of asthma is generally not achieved without control of upper airway disease [8].

Rhinitis may also precede the diagnosis of asthma with the relative risk of subsequent asthma development increased by 2.7–3.5 in a study [11▪] of 6461 adults, aged 20–44 years. Rhinitis also may precede severe rhinosinusitis, nasal polyposis, and asthma associated with nonsteroidal anti-inflammatory drugs. The mechanism linking the development or exacerbation of asthma in individuals with upper airway disease may be multifactorial, including release of systemic immune mediators from the upper airway, drainage of inflammatory mediators from the upper airway into the lower airway, neurogenic responses resulting in more generalized airway inflammation or common inhalant mechanisms with allergens causing inflammation initially in the upper airway followed by lower airway involvement. Inflammation develops in the nasal airway following select allergen bronchial challenge in allergic patients and vice versa [12,13]. All of these mechanisms may be involved or the mechanism may vary with differing types of rhinitis or rhinosinusitis.

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Diagnostic and therapeutic considerations

The primary symptom of rhinitis or rhinosinusitis likely confused with asthma is cough. This is a particular challenge because almost all persistent asthmatic patients have rhinitis or rhinosinusitis and cough is a frequent problem with asthma as well. Persistent asthma can suggest that greater consideration be given to optimal management of the upper airway disease. Utilization of systemic therapies, such as oral leukotriene modifiers, allergen immunotherapy or omalizumab, and allergen avoidance, may simultaneously address the treatment of both the upper airway and asthma. Sleep disturbance, a common comorbidity with asthma, is also a complication of persistent nasal obstruction [14].

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An increase of retrograde movement of gastric contents into the esophagus is termed GERD or if the refluxate reaches the larynx, laryngopharyngeal reflux. Gastroesophageal reflux is a normal physiologic phenomenon and is termed GERD only when the frequency and duration of acid refluxate exceed a defined parameter. The reflux events are generally quantified with a pH probe placed in the esophagus. The prevalence of GERD in the general adult population is 10–20% in western countries but approximately 5% in Asia. The prevalence of GERD in pediatric studies is 2–8%.

Atypical symptoms of GERD include throat tightness, throat clearing, cough, chest tightness, and hoarseness. Some individuals will describe a sensation of postnasal drip, suggesting upper airway disease as a source. The cough with laryngopharyngeal reflux will usually be described as originating in the larynx or pharynx rather than the chest, but this distinction is subject to patient perception and some will describe the cough as originating in the chest.

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Relationship with asthma

There is a confirmed relationship of GERD and asthma as well as GERD with upper airway complaints [15▪,16]. The nature of this relationship, specifically if there is causality between airway dysfunction and GERD, is less clear. Epidemiologic studies demonstrate a variable prevalence of GERD in individuals with asthma, ranging from 12 to 85%, with some of the variation due to the definition of GERD. Conversely, asthma is reported more commonly in individuals with GERD. There is also evidence of increased upper airway complaints in individuals with GERD [16]. Asthma therapies, particularly theophylline and albuterol, may decrease lower esophageal sphincter tone, suggesting asthma therapy may increase GERD.

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Diagnostic or therapeutic considerations

GERD may pose diagnostic challenges in that cough, laryngeal or pharyngeal irritation, and chest tightness are common symptoms in individuals with asthma and/or GERD and/or upper airway disease. Thus, the symptoms of GERD may be misinterpreted as asthma or rhinitis both when making a diagnosis and when monitoring patients for control of their respiratory disease.

There is conflicting evidence that therapy of GERD improves asthma. Double-blind, prospective, controlled trials demonstrate that treatment of asymptomatic GERD does not improve asthma in adults or children [17▪▪,18▪]. Treatment of GERD in double-blind studies [19,20] of individuals with asthma and symptomatic GERD shows a benefit for asthma quality of life and number of exacerbations but inconsistent effects on asthma symptoms, albuterol use, and pulmonary function. Cochrane review of all controlled trials of GERD therapy in adults and children with asthma found a lack of benefit in achieving asthma control, although there is a suggestion of reduced albuterol use and clinical benefit in an undefined subset of affected individuals [21]. Finally, asthma or asthma therapy may aggravate or appear to aggravate GERD as bronchodilators may reduce esophageal sphincter tone, systemic corticosteroids may increase gastric acid production, and inhaled corticosteroids may cause hoarseness similar to the hoarseness caused by GERD.

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VCD is defined by the complete or partial adduction or closure of the vocal folds with inspiration and/or expiration. This maladaptive process is not usually volitional but seems to occur in response to irritation of the larynx or hypopharynx or secondary to emotional or physical stress. The symptoms of VCD include wheezing, usually more prominent with inspiration, hoarseness, dysphonia, cough, and globus pharyngeus. Affected individuals will frequently describe their ‘chest tightness’ as originating superior to the sternal notch. Symptoms are often episodic with rapid resolution, with or without therapy. The wheeze may be high pitched and musical or stridorous. The symptoms may be provoked by respiratory or laryngeal irritants, exercise, stress, or anxiety. Frequent use of inhalers may contribute as the larynx may be irritated by such therapies.

Prevalence is difficult to determine as VCD is a dynamic, episodic condition, which may not be evident or easily provoked at the time of the examination. There is one report using histamine inhalation challenge as a means of identifying ‘hyperreactivity’ of the larynx [22▪]. Exercise is a common trigger of VCD in extreme or elite athletes, often misdiagnosed as exercise-induced bronchospasm.

The appearance of the larynx during active symptoms shows the true or false vocal folds or both adducted during ventilation (Fig. 1). The most severe form of the adduction results in a small, diamond-shaped opening between the vocal folds, termed ‘chink deformity’. Other suggestions of VCD are inflammation of the larynx or variable motion or quivering of the vocal folds during quiet ventilation or during forced inhalation or exhalation. The inflammation of the larynx can be associated with GERD or laryngopharyngeal reflux, another potential comorbidity with VCD. Treatment of GERD may improve VCD, but this has not been confirmed in prospective trials. Biofeedback therapy enables the affected individual to employ relaxation techniques to minimize muscle tension in the larynx, usually resulting in relief of symptoms and resolution of wheeze.

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Relationship with asthma

Patients may be misdiagnosed with asthma when VCD is responsible for their symptoms or have VCD and asthma simultaneously, a more common occurrence in the authors’ opinion. Distinguishing the two conditions is challenging and may require direct visualization of the vocal folds during a symptomatic episode to be certain of the diagnosis.

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Diagnostic or therapeutic considerations

Any patient with difficult-to-control asthma should be assessed for VCD. The use of the flow volume loop may be helpful in recognizing VCD [23▪▪]. The inspiratory loop typically exhibits decreased flow rate with variability in flow, resulting in a wavy, flattened curve instead of the typical smooth, oval appearance (Fig. 2). None of these findings is individually definitive but helpful if the diagnosis is suspected. The only method for confirmation is to visualize the vocal folds, usually with a flexible nasolaryngoscope, during symptoms. Psychological dysfunction is a significant contributor or predisposing factor in VCD and, thus, contributes to the association of asthma symptoms with anxiety and depression [24].

Factors associated with VCD are as follows:

1. Anxiety disorders

2. Family members of healthcare professionals

3. History of psychiatric disease, particularly depression

4. Perfectionists or obsessive/compulsive personalities

5. Victims of remote sexual abuse or trauma.

Clinical suspicion and careful evaluation are necessary as there is no single measurement or test to confirm the diagnosis other than direct visualization of the vocal cords during symptoms. A speech therapist or speech pathologist, knowledgeable about VCD can be very helpful in treating this disorder.

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Chronic obstructive lung disease (COPD) is characterized by airflow obstruction that is not fully reversible. Sixty percent of participants in COPD trials exhibit 15% improvement in forced expiratory volume in one second with aggressive bronchodilator therapy but not improvement to normal. This condition is associated with cigarette smoking, but up to 15–20% of affected individuals do not have a significant history of cigarette smoking. Only a minority of cigarette smokers develop COPD indicating that host factors, in addition to irritants from the cigarette smoke, are essential for disease development. Approximately 24 million people in the United States were estimated to have COPD in 2008, and probably less than 50% of those affected are diagnosed at any given time. In the United States alone, 672 000 hospitalizations for COPD occurred in 2006 and 124 477 deaths in 2007. COPD was the third leading cause of death in the United States, and worldwide COPD is the fourth or fifth most common cause of death.

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Relationship to asthma

The symptoms of COPD and asthma are very similar: cough, mucous production, and shortness of breath. Although wheezing is associated with asthma, individuals with COPD frequently wheeze and all asthma patients do not wheeze. This diagnostic challenge is further compounded by a subset of asthmatic patients who develop irreversible airflow obstruction, resembling COPD.

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Diagnostic or therapeutic considerations

Onset of symptoms prior to the age of 30 years, a personal or family history of atopic disease, upper airway disease, and mucosal and/or peripheral blood eosinophilia support a diagnosis of asthma. Cigarette smoking increases the likelihood of COPD. Having both conditions is not unusual. Treatment of both obstructive airway conditions is similar, although the focus for COPD is regular bronchodilator therapy with inhaled corticosteroids added for more severe disease. This contrasts with the recommendation to utilize anti-inflammatory therapy early in the asthmatic disease process and to avoid regular use of bronchodilator therapy. Inhaled anticholinergic therapy is approved in COPD but not asthma, although anticholinergic therapy is effective in asthma [25,26▪▪,27,28▪▪].

In summary, COPD and asthma share clinical features confounding the diagnosis of the two conditions. Although COPD and asthma are viewed by some as totally separate conditions, others consider these disorders as part of a continuum of airflow obstruction. Treatment approaches are similar with the exceptions noted.

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Obesity is common and increasing in prevalence worldwide. Obesity is generally defined by BMI, weight in kilogram divided by height in meters squared. Normal weight is defined as less than 25 kg/m2, overweight, 25–30 kg/m2, and obesity, greater than 30 kg/m2. There are some concerns with this definition as central obesity may have more influence on health than total weight. Fat cells appear to modify inflammation and the role of adipocytes varies according to the type of fat or location of the cell [29,30].

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Relationship with asthma

Multiple studies have attempted to characterize the association of increased body weight and asthma in both children and adults. The majority of peer-reviewed articles in the literature demonstrate a relationship with obesity and both the development and increased severity of asthma. In most of these papers, obesity precedes asthma [31,32]. The National Asthma Survey, published in 2008 and reporting data from 3095 participants, describes a persistence of symptoms, increased work absence, greater use of inhaled beta agonists and corticosteroids, and decrease in asthma control in individuals with greater body mass compared with normal weight asthmatic patients [33]. The mechanism by which obesity influences asthma or asthma symptoms is not established, with possibilities including a modified inflammatory response, increased asthma symptoms due to weight and deconditioning, functional effects on breathing mechanics or decreased response to inhaled corticosteroids [32,34]. There are data to support each possibility but no confirmation of the most important factor [35].

Another consideration is the misdiagnosis of asthma in the presence of obesity. Symptoms of shortness of breath, exercise-induced dyspnea, and chest tightness as a result of obesity may be misattributed to asthma, resulting in an incorrect diagnosis. Other publications demonstrate that misdiagnosis is as common, up to 30%, in normal weight as in obese individuals, refuting the greater likelihood of misdiagnosis of asthma in obese individuals [36▪,37,38].

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Diagnostic and therapeutic considerations

The therapy of asthma is not modified specifically by increased weight but ideal outcomes are dependent on losing weight. The most effective therapy for asthma, inhaled corticosteroids, may be less effective in the obese individual [34]. This observation does not warrant a modification of the treatment strategy but may prompt the consideration of adding noncorticosteroid therapies to the obese asthmatic. Facilitating weight loss is an ideal but the reality is that most affected individuals cannot lose weight, and if they do so, they usually regain it. Nevertheless, the clinician should encourage weight reduction strategies or consider surgical approaches [39,40].

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Chronic disease in general is associated with psychological dysfunction, most commonly depression and anxiety [41▪]. Anxiety, with or without depression, is the psychological dysfunction most commonly linked to asthma [42▪▪]. Anxiety is generally defined in the clinical literature with validated questionnaires, whereas in clinical practice the definitions are usually not quantitative. Anxiety and depression are common in the general community with estimates of 9.5% of US adults having depression at any given time and over 20% with a lifetime prevalence and 18% with anxiety disorder, and 29% with a lifetime prevalence ( There is significant overlap of these two conditions such that the combined prevalence is less than the sum of the two.

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Relationship with asthma

Anxiety and/or depression and panic disorder are reported in 16–52% of the population with asthma. A World Health Organization survey of 85 000 adults in 17 countries using a standardized, structured psychiatric interview with trained interviewers reported an OR of 1.6 (95% confidence interval 1.4–1.8) for depression and 1.5 (95% confidence interval 1.4–1.7) for anxiety disorders in asthma. Other studies [42▪▪] describe a stronger relationship with anxiety rather than depression, although the presence of both has the greatest effect on asthma outcomes. Studies [43,44] also suggest a relationship of attention deficit disorder with asthma in both children and adults.

Limited longitudinal studies report that anxiety and depression increase the likelihood of developing asthma, and asthma is a risk factor for developing anxiety and depression. Some studies are limited by the absence of objective measures of asthma. A community-based study [45] in Switzerland reported that asthma increased the subsequent development of panic disorder by 4.5, and panic disorder increased the subsequent onset of asthma, with an OR of 6.3. A US study [46] of 5000 adults confirmed that anxiety and depression increased the risk of developing spirometry-confirmed asthma. The bidirectional risk of asthma and psychologic dysfunction was confirmed in a meta-analysis of pediatric studies. The development of asthma is more likely with a history of behavioral problems, and the development of behavioral problems is more likely with a preceding diagnosis of asthma [47].

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Diagnostic and therapeutic considerations

Asthma control is negatively associated with the comorbidity of anxiety with or without depression [48▪]. Depression or anxiety is found in more than 50% of individuals with difficult-to-treat asthma [49]. Medication adherence or modified symptom awareness may explain the relationship. Asthma deaths show a bimodal variation with age with one peak in adolescence, and this is likely due to psychological stressors affecting medication compliance or symptom awareness during the teenage years. Asthma control is based upon lung function, measured intermittently, and symptoms, which are the most consistent factor used by patients and clinicians to adjust asthma medications and assess control. Vague asthma symptoms, such as chest tightness or breathing difficulties, are frequently reported by individuals with anxiety without asthma. The variability of lung function confounds the problem because normal lung function does not exclude asthma as being responsible for symptoms. The common association of anxiety, with or without depression, in asthma confounds the interpretation of survey data assessing the control of asthma, as these studies depend almost exclusively on patient-reported symptoms. Finally, asthma therapy may be less effective with concomitant psychologic dysfunction due to corticosteroid resistance or enhanced inflammatory cell activity [50,51▪].

The recognition of depression or anxiety in individuals with asthma may not be optimal. A Canadian study [52] of asthma showed that fewer than 20% of individuals with psychiatric disease were receiving therapy and less than 15% had been evaluated by a mental health specialist.

Treatment of anxiety and depression may improve asthma. A Cochrane review in 2006 reported inconclusive improvement of asthma with cognitive behavioral modification, counseling, and relaxation therapy with or without biofeedback. Small studies [53] of panic control programs or antidepressant medication suggest beneficial effects in asthma management. Aerobic exercise training reduces stress and improves depression scores as well as increases asthma symptom-free days and improves asthma health status. Although definite recommendations cannot be offered, common sense and clinical experience indicate that reduction of anxiety and depression improve asthma outcomes either by changing the perception of symptoms, improving compliance or modifying the asthma.

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Multiple additional factors may influence the diagnosis or management of asthma (Table 1 and list ‘Diseases, conditions or medications that result in shortness of breath or cough’). These are too numerous to mention individually in this review. They can generally be divided into conditions that are associated with cough and mucous production and those associated with shortness of breath or dyspnea. Most of the diseases in Table 1 will improve with systemic corticosteroids and occasionally with high-dose inhaled corticosteroids but do not demonstrate the typical spirometry findings or reversibility of asthma.

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Asthma is a common condition that is very responsive to appropriate therapy. Confirmation of the diagnosis by history, physical examination, and spirometry with a flow volume loop is essential, as the symptoms of asthma are common in many other conditions. Recognizing the comorbidities will facilitate reaching the goal of asthma control, avoid the complications of adverse effects that arise from the other conditions, and limit the side-effects of inappropriate doses of therapeutics such as systemic corticosteroids. Asthma comorbidities require physicians to approach each patient with the perspective of a generalist.

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Conflicts of interest

For this article there are no conflicts of interest. D.K.L. declares the following: Consultant: AstraZeneca, Genentech. Speaker Bureau: Genentech, TEVA. Clinical Trials: Forest, Genentech, Merck, ViroPharma. Expert Legal Review: asthma death. Publications: Associate Editor Journal of Allergy and Clinical Immunology, Editorial Board of Annals of Allergy Asthma and Immunology, Editorial Board of Journal of Allergy and Clinical Immunology: In Practice Organizations: Board of Directors American Academy of Allergy Asthma and Immunology.

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Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 122–123).

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1▪. Demoly P, Gueron B, Annunziata K, et al. Update on asthma control in five European countries: results of a 2008 survey. Eur Respir Rev 2010; 19:150–157.

This survey of asthma care in Europe shows that optimal control is frequently not achieved despite the use of guideline therapy.

2. Fuhlbrigge A, Reed ML, Stempel DA, et al. The status of asthma control in the U.S. adult population. Allergy Asthma Proc 2009; 30:529–533.
3▪▪. Boulet LP. Influence of comorbid conditions on asthma. Eur Respir J 2009; 33:897–906.

This study provides a review of the multiple comorbidities that may influence asthma. These include allergen exposure if allergic, bronchiectasis, cigarette smoking and other irritant exposure, COPD, gastroesophageal reflux, hormonal disturbance, hyperventilation syndrome and laryngeal dysfunction, obesity, psychopathologies, recurrent respiratory infections, sleep apnea, and upper airway disease.

4. Thomas M, Price D. Impact of co-morbidities on asthma. Expert Rev Clin Immunol 2008; 4:731–742.
5▪▪. ten Brinke A, Sterk PJ, Masclee AA, et al. Risk factors of frequent exacerbations in difficult-to-treat asthma. Eur Respir J 2007; 26:812–818.

In this small, cross-sectional study, 152 patients with difficult-to-treat asthma, aged 18–75 years, were recruited from 10 outpatient pulmonary clinics in the Netherlands. Sixteen patients refused participation and 44 were not included in analysis due to inability to determine exacerbations in patients on continual systemic corticosteroids. A self-reported questionnaire assessed psychological function. The clinical evaluation included esophageal pH probe in select participants, total and specific IgE to common aeroallergens and food antigens, humoral immune assessment with quantitative immunoglobulins, ENT consultation to evaluate sinus disease, which included rhinolaryngoscopy or sinus computed tomography scan, inhaler technique assessment and spirometry. ORs for exacerbations of asthma were determined by logistic regression analyses and the findings showed OR 3.4 for obstructive sleep apnea, OR 3.7 for severe nasal sinus disease, OR 4.9 for gastro-esophageal reflux, OR 6.9 for recurrent respiratory infections, and OR 10.8 for psychological dysfunction. Severe, chronic sinus disease and psychological dysfunctioning were the only independently associated factors (adjusted OR 5.5 and 11.7, respectively).

6▪▪. Gershon AS, Guan J, Wang C, et al. Describing and quantifying asthma comorbidity: a population study. Plos One 2012; 7:e34967.

This report is a population study of administrative data of approximately 12 million individuals, 1.5 million with asthma, living in Ontario, Canada. Asthma comorbidities were quantified. In all age groups, there were increased claims for all respiratory diseases other than asthma; psychiatric disease in individuals less than 4 and 18–44 years of age; metabolic, immunologic, and hematologic disorders in individuals less than 4 years; and perinatal disorders in individuals 17 years and less.

7. Bresciani M, Paradis L, Des Roches A, et al. Rhinosinusitis in severe asthma. J Allergy Clin Immunol 2001; 107:73–80.
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11▪. Shaaban R, Zureik M, Soussan D, et al. Rhinitis and onset of asthma: a longitudinal population-based study. Lancet 2008; 372:1049–1057.

This paper reports a longitudinal, population-based study including 14 countries in western Europe. The data show an increased relative risk of developing asthma over 8.8 years with preceding atopy and rhinitis, 1.63 for atopy, 2.71 for nonallergic rhinitis, and 3.53 for allergic rhinitis. Allergic rhinitis with dust mite allergy was the unique sensitivity that increased risk of developing asthma.

12. Braunstahl GJ, Kleinjan A, Overbeek SE, et al. Segmental bronchial provocation induces nasal inflammation in allergic rhinitis patients. Am J Respir Crit Care Med 2000; 161:1051–2057.
13. Braunstahl GJ, Overbeek SE, Kleinjan A, et al. Nasal allergen provocation induces adhesion molecule expression and tissue eosinophilia in upper and lower airways. J Allergy Clin Immunol 2001; 107:469–476.
14. Koinis-Mitchell D, Craig T, Esteban CA, Klein RB. Sleep and allergic disease: a summary of the literature and future directions for research. J Allergy Clin Immunol 2012; 130:1275–1281. doi: 10.1016/j.jaci.2012.06.026.
15▪. Havemann BD, Henderson CA, El-Serag HB. The association between gastro-oesophageal reflux disease and asthma: a systematic review. Gut 2007; 56:1654–1664.

This paper describes a thorough review of the medical literature extant as of 2006. The conclusion was there is a relationship between GERD and asthma, but the nature of the relationship or causality is not understood. Abnormal pH probe studies, esophagitis, and hiatal hernia are common in asthma, but asthma is not common in individuals with GERD.

16. Theodoropoulos DS, Ledford DK, Lockey RF, et al. Prevalence of upper respiratory symptoms in patients with symptomatic gastroesophageal reflux disease. Am J Respir Crit Care Med 2001; 164:72–76.
17▪▪. Mastronarde JG, Anthonisen NR, Castro M, et al. American Lung Association Asthma Clinical Research CentersThis study assessed the efficacy of esomeprazole for treatment of poorly controlled asthma. N Engl J Med 2009; 360:1487–1499.

This paper describes a double-blind, prospective trial in adults with asthma and no symptoms of GERD demonstrating the lack of efficacy of treating with acid suppression to improve asthma control. Acid suppression was similarly ineffective in individuals with asymptomatic GERD and individuals without GERD.

18▪. Holbrook JT, Wise RA, Gold BD, et al. Writing Committee for the American Lung Association Asthma Clinical Research CentersLansoprazole for children with poorly controlled asthma: a randomized controlled trial. JAMA 2012; 307:373–381.

This double-blind, prospective trial in children with asthma and without symptoms of GERD demonstrates the lack of benefit in treating asymptomatic GERD for improving asthma control.

19. Littner MR, Leung FW, Ballard ED 2nd, et al. Lansoprazole Asthma Study GroupEffects of 24 weeks of lansoprazole therapy on asthma symptoms, exacerbations, quality of life and pulmonary function in adult asthmatic patients with acid reflux symptoms. Chest 2005; 128:1128–1135.
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22▪. Bucca CB, Bugiani M, Culla B, et al. Chronic cough and irritable larynx. J Allergy Clin Immunol 2011; 127:412–419.

This paper describes a technique to identify and quantify laryngeal hyperreactivity in individuals with an upper airway cough, which may be associated with paradoxical vocal cord motion.

23▪▪. Watson MA, King CS, Holley AB, et al. Clinical and lung-function variables associated with vocal cord dysfunction. Respir Care 2009; 54:467–473.

This paper describes a 3-year prospective trial in which pulmonologists interpreting the spirometry were blinded as to the results of rhinolaryngoscopy. No specific spirometry finding was statistically predictive of VCD, although the ratio of inspiratory flow rate at 25% of the inspired volume compared with the expiratory flow rate at 75% of the vital capacity was the best predictor available [OR 1.97 (confidence interval 1.12–3.44)]. The conclusion was that rhinolaryngoscopy should be considered in suspected asthma with normal or near normal spirometry, particularly if inspiratory dysfunction was noted.

24. Husein OF, Husein TN, Gardner R, et al. Formal psychological testing in patients with paradoxical vocal fold dysfunction. Laryngoscope 2008; 118:740–747.
25. Bateman ED, Kommann O, Schmidt P, et al. Tiotropium is noninferior to salmeterol in maintaining improved lung function in B16-Arg/Arg patients with asthma. J Allergy Clin Immunol 2011; 128:315–322.
26▪▪. Peters SP, Kunselman SJ, Icitovic N, et al. National Heart, Lung, and Blood Institue Asthma Clinical Research NetworkTiotropium bromide step-up therapy for adults with uncontrolled asthma. N Engl J Med 2010; 363:1715–1726.

This study provides excellent evidence that anticholinergic therapy is an effective option in the management of chronic asthma. The paper does not address adding anticholinergic therapy to long-acting beta agonist treatment.

27. Novelli F, Malagrinò L, Dente FL, Paggiaro P. Efficacy of anticholinergic drugs in asthma. Expert Rev Respir Med 2012; 6:309–319.
28▪▪. Kerstjens HAM, Engel M, Dahl R, et al. Tiotropium in asthma poorly controlled with standard combination therapy. N Engl J Med 2012; 367:1198–1207.

This report presents the results of two industry supported, multicenter, double-blind, randomized trials of asthma. The studies were well designed. Prior to entry, participants were not well controlled despite receiving combination therapy with inhaled corticosteroids and long-acting beta agonists. The results demonstrate that the addition of a long-acting anticholinergic, tiotropium, increased the time to the first severe asthma exacerbation and reduced the overall risk of a severe asthma exacerbation, significant clinical outcomes. In addition, there was a modest, sustained bronchodilation effect.

29. Shore SA. Obesity and asthma: possible mechanisms. J Allergy Clin Immunol 2008; 121:1087–1093.
30. Pakhale S, Doucette S, Vandemheen K, et al. A comparison of obese and nonobese people with asthma: exploring an asthma-obesity interaction. Chest 2010; 137:1316–1322.
31. Guh DP, Zhang W, Bansback N, et al. The incidence of co-morbidities related to obesity and overweight: a systematic review and meta-analysis. BMC Public Health 2009; 9:88.
32. Lessard A, Turcotte H, Boulet LP. Obesity and asthma: a specific phenotype? Chest 2008; 134:317–323.
33. Taylor B, Mannino D, Brown C, et al. Body mass index and asthma severity in the National Asthma Survey. Thorax 2008; 63:14–20.
34. Sutherland ER, Goleva E, Strand M, et al. Body mass and glucocorticoid response in asthma. Am J Respir Crit Care Med 2008; 178:682–687.
35. Farah CS, Salome CM. Asthma and obesity: a known association but unknown mechanism. Respirology 2012; 17:412–421.
36▪. Aaron SD, Vandemheen KL, Boulet LP, et al. Over diagnosis of asthma in obese and nonobese adults. CMAJ 2008; 179:1121–1131.

The diagnosis of asthma was excluded in 28.7% of 254 nonobese individuals with a physician diagnosis of asthma and in 31.8% of 242 obese individuals with a diagnosis of asthma. These data do not support an increase in the misdiagnosis of asthma in obese individuals.

37. Lang JE, Feng H, Lima JJ. Body mass index-percentile and diagnostic accuracy of childhood asthma. J Asthma 2009; 46:291–299.
38. Scott S, Currie J, Albert P, et al. Risk of misdiagnosis, health-related quality of life, and BMI in patients who are overweight with doctor-diagnosed asthma. Chest 2012; 141:616–624.
39. Eneli IU, Skybo T, Camargo CA Jr. Weight loss and asthma: a systematic review. Thorax 2008; 63:671–676.
40. Maniscalco M, Zedda A, Faraone S, et al. Weight loss and asthma control in severely obese asthmatic females. Respir Med 2008; 102:102–108.
41▪. Atlantis E, Sullivan T, Sartorius N, Almeida OP. Changes in the prevalence of psychological distress and use of antidepressants or antianxiety medications associated with comorbid chronic diseases in the adult Australian population, 2001–2008. Aust N Z J Psychiatry 2012; 46:445–456.Epub 2012 Jan 5.

This study reports the result of a survey of more than 48 000 adults with psychological stress quantitated with a standardized questionnaire and chronic diseases self-reported. Diabetes, cardiovascular disease, cancer, and asthma were more likely in individuals with psychological stress, and psychological dysfunction was even more likely in the presence of more than one chronic disease. Between 2001 and 2008, the prevalence of psychological disease increased most for those with diabetes and cardiovascular disease.

42▪▪. Wang G, Zhour T, Wang L, et al. Relationship between current psychological symptoms and future risk of asthma outcomes: a 12-month prospective cohort study. J Asthma 2011; 48:1041–1050.

This prospective 12-month study of 297 patients with asthma showed that anxiety combined with depression independently predicts the future risk of poor asthma outcomes. The relative risk for an unplanned asthma visit or emergency department visit was 2.33 (confidence interval 1.50–3.1) and 3.13 (confidence interval 1.90–5.17), respectively, for anxiety with depression, but the relative risk was not statistically increased for individuals with either anxiety or depression.

43. Fasmer OB, Halmøy A, Eagan TM, et al. Comorbidity of asthma with ADHD. BMC Psychiatry 2011; 11:128.
44. Fasmer OB, Halmoy A, Eagan TM, et al. Adult attention deficit hyperactivity disorder is associated with asthma. BMC Psychiatry 2011; 11:128Published online 2011 August 7. doi: 10.1186/1471-244X-11-128.
45. Hasler G, Gergen PJ, Kleinbaum DG, et al. Asthma and panic in young adults: a 20-year prospective community study. Am J Respir Crit Care Med 2005; 171:1224–1230.Epub 2005 Mar 11.
46. Goodwin RD, Chuang S, Simuro N, et al. Association between lung function and mental health problems among adults in the United States: findings from the First National Health and Nutrition Examination Survey. Am J Epidemiol 2006; 165:383–388.
47. Tibosch MM, Verhaak CM, Merkus PJFM. Psychological characteristics associated with the onset and course of asthma in children and adolescents: a systematic review of longitudinal effects. Patient Educ Couns 2011; 82:11–19.
48▪. Urrutia I, Aguirre U, Pascual S, et al. Impact of anxiety and depression on disease control and quality of life in asthma patients. J Asthma 2012; 49:57–62.Epub 2011 Dec 16.

This cross-sectional study of a limited population in Spain shows that asthma control was decreased in individuals with anxiety and depression. Anxiety had an independent effect on quality of life across all domains but anxiety combined with depression had a greater magnitude of effect.

49. Heaney LG, Conway E, Kelly C, Gamble J. Prevalence of psychiatric morbidity in a difficult asthma population: relationship to asthma outcome. Respir Med 2005; 99:1152–1159.
50. Jaczku A, Panettieri RA Jr. Social stress and asthma: the role of corticosteroid insensitivity. J Allergy Clin Immunol 2010; 125:550–558.
51▪. Theoharides TC, Enakuaa S, Sismanopoulos N, et al. Contribution of stress to asthma worsening through mast cell activation. Aust N Z J Psychiatry 2012; 46:445–456.Epub 2012 Jan 5.

Discussion of an interesting hypothesis that stress, through corticotropin-releasing hormone, may modulate mast cell activity and increase asthma.

52. Goodwein RD, Pagura J, Cox B, Sareen J. Asthma and mental disorders in Canada: impact on functional impairment and mental health service use. J Psychosom Res 2010; 68:165–173.
53. Yorke J, Felming SL, Shuldham C. A systematic review of psychological interventions for children with asthma. Pediatr Pulmonol 2007; 42:114–124.

asthma; asthma control; comorbidities

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