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.
CLINICAL IMPORTANCE OF COMORBIDITIES
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.
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
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
11. Obstructive lung disease (COPD)
12. Paradoxical vocal fold movement [vocal cord dysfunction (VCD)]
14. Psychologic disease (anxiety, depression, behavioral disorders)
15. Respiratory infection
16. Rhinitis and rhinosinusitis
UPPER AIRWAY DISEASE
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 .
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.
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 . 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 .
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.
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 .
GASTROESOPHAGEAL REFLUX DISEASE
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.
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 . Asthma therapies, particularly theophylline and albuterol, may decrease lower esophageal sphincter tone, suggesting asthma therapy may increase GERD.
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 . 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.
PARADOXICAL VOCAL FOLD MOVEMENT (VOCAL CORD DYSFUNCTION)
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.
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.
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 .
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.
CHRONIC OBSTRUCTIVE LUNG DISEASE
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.
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.
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.
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].
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 . 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 .
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].
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 . 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].
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 (http://www.nihm.nih.gov/statistics). There is significant overlap of these two conditions such that the combined prevalence is less than the sum of the two.
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  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  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 .
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 . 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  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  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.
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.
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.
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.
REFERENCES AND RECOMMENDED READING
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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