Comorbid disease in asthma: the importance of diagnosis

William Osler’s comprehensive definition of bronchial asthma as “a neurotic affection characterized by hyperemia and turgescence of the mucosa of the smaller bronchial tubes … a peculiar exudate of mucin attacks … due to direct irritation of the bronchial mucosa or induced reflexly, by irritation of the nasal mucosa, and indirectly by reflex influences from stomach, intestines or genital organs” has been chiseled away to a chronic inflammatory disorder of the airways [1].

Asthma’s sharp climb in developing countries parallels their growing urbanization and westernization, eclipsing its rising prevalence in developed nations. Disease morbidity and mortality is higher in low- and lower–middle-income countries [101] particularly among the elderly, where atypical presentations and comorbidities render it likely to be underdiagnosed [2]. Common comorbidities associated with frequent exacerbations in difficult-to-treat asthma include hiatus hernia with or without associated gastroesophageal reflux disease (GERD), rhinosinusitis, recurrent respiratory infections, psychological disturbances and obstructive sleep apnea (OSA) [3,4]. Undiagnosed comorbid disease influences diagnosis, treatment response, disease management and control of asthma.

Organ/system comorbidity

Atopy syndrome

Atopy and asthma initiated during early life develop into persistent childhood wheeze, related to early infections and sensitization. High mite-specific IgE titers at the age of 2 years are associated with a 12.7% risk of persistent wheeze, increasing progressively to 87.2% by 5 years with severe lower respiratory tract infections [5].

Upper respiratory tract disease

Allergic rhinitis

Progressive upper airway inflammatory pathology in the lung manifests as a common disease process, supporting genesis of the one airway concept [6]. Allergic rhinitis (AR), unquestionably asthma’s most common comorbidity, exacerbates asthma symptoms and disease severity, and increases asthma-related hospitalizations, general practitioner and emergency department visits, and overall asthma-related drug costs [7,8]. Even though 89.5% of asthmatics are afflicted with AR [9], it often goes undetected. Proportionally half of Caribbean children with asthma attending primary care facilities are estimated to have undiagnosed AR [10]. Despite family physicians being the first point of contact for the diagnosis of rhinitis, it is underdiagnosed in primary care [11]. Asthma and AR are epidemiologically connected by increasing prevalence, shared quality-of-life issues and significant comorbidity; AR often precedes asthma.

Viral infections

Viral bronchiolitis linked to the initiation of persistent wheeze identifies those children who are at increased risk for wheezing. Although respiratory syncytial virus (RSV) remains the main primary infectious agent associated with childhood wheeze, rhinovirus (RV), which was once considered a strictly upper airway pathogen, is now a recognized lower airway infectious agent. RV-induced wheezing illness in the first year of life is a strong predictor of later wheezing in the third year of life. Risk factors for wheezing at 3 years of age include at least one wheezing illness with RSV, RV and/or non-RV/RSV pathogens in infancy, with recovery of RV being the most frequent among viral pathogens [12]. A third of Caribbean children with acute wheeze expressed RV and RSV as the most predominant viral pathogens, signifying that they are notable in both tropical and temperate climates [13]. ‘Colds’ in asthmatic children should receive attention as heralds of emergent acute wheeze. The linkage between asthma, viral upper respiratory tract infection, AR and sinusitis is strong, and asthma is a suspected possible sequel to these conditions. Conversely, these comorbidities are likely to be triggers of intermittent or persistent asthma. Thus, treatment and control of upper airway disease may improve outcomes for asthma patients.

Vocal cord dysfunction

Vocal cord dysfunction, a paradoxical movement of the vocal cords during inspiration, mimics asthma. Laryngoscopy matched by high-resolution dynamic volume computerized tomography informs on accurate diagnosis [14].

Lower respiratory tract disease

Infections

Chlamydophila pneumoniae infection is a recently suggested etiology for severe asthma in cold and warm climates [15,16]. Telithromycin failed to change chlamydial titers, however, asthma symptom resolution was found to occur earlier in the ketolide arm of this trial [15]. C. pneumoniae probably enhances neutrophilic airway inflammation in early life [17,18].

Chronic obstructive respiratory disease

The shared symptom similarity of asthma and chronic obstructive pulmonary disease (COPD) facilitates misdiagnosis of one condition for the other. At least a third of registered asthmatics in specialty care [19] and half in primary care [20] have a spirometry-based study diagnosis of COPD. Although the two conditions are thought to coexist in the presence of incomplete reversibility, on follow-up, coexistence is unlikely and can be differentiated [21]. Encouraging primary healthcare providers to evaluate pulmonary lung function in the asthmatic patient can avoid inefficient management resulting from missed diagnosis. Nonasthmatic chronic respiratory disease can be missed, calling for more attention from the health service and multifaceted health management strategies.

Obesity & its associated morbidities

Obesity

Obesity and asthma share partnership in pulmonary morbidity. Abnormalities in ventilation distribution, airway closure in the dependent zones of the lung, ventilation perfusion inequalities from reduced expiratory reserve volume and functional residual capacity can ensue [22]. Adipocytes and adipose tissue macrophages are recruited to obese adipose tissue and signify the chronic inflammatory nature of obesity. Leptin, adiponectin and TNF-α (overexpressed in adipose tissue) are important adipokines contributing to airway hyperresponsiveness [23–25]. Furthermore, the inflammatory environment in obesity modifies the clinical and biologic glucocorticoid response [26].

Common genetic mechanisms may ascertain the relationship between obesity and asthma. Identified candidate genes associated with obesity and asthma include, but are not limited to, the β₂-receptor, the glucocorticoid receptor, TGF-β and peroxisome proliferator-activated receptor-γ [27]. Phenotyping and longitudinal cohort studies could determine the risk attributed to developing asthma-driven obesity and cause–effect relationships. The obesity–asthma linkage may uncover novel therapeutic strategies for obese asthmatic subjects.

Obstructive sleep apnea

Obesity is a risk factor for OSA in both children and adults. From the accumulating evidence of an association between obesity and asthma, OSA is an independent risk factor for asthma exacerbations [27]. Dyspnea from OSA-induced cardiac dysfunction, neuromechanical reflex bronchoconstriction with enhanced vagal tone, GERD and inflammation (local and systemic) can trigger and worsen asthma control.VEGF-induced airway angiogenesis, leptin-related airway changes and OSA-induced weight gain are determinants of the causal linkage between the morbidities of OSA and asthma [28]. OSA compounds asthma management, and treating asthma alone in obese subjects, without addressing obesity, enhances the challenge of disease control.

Gastroesophageal reflux disease

Gastroesophageal reflux disease confounds asthma control. It seems to trigger nocturnal asthma and is evidenced by improved peak expiratory flow rate in subjects with nocturnal asthma and GERD after treatment with esomeprazole [29]. Distal esophageal acidification causes vagal stimulation and consequent reflex bronchoconstriction, independent of airway microaspiration. Asthma symptoms also follow from aspiration into the proximal airways after acid reflux into the esophagus. More asthmatic patients in the general population have GERD. Many of them, with a diagnosis confirmed by pH probe, do not experience classical GERD symptoms and are, therefore, considered to have ‘silent GERD’ [30]. Double-dose proton pump inhibitor (PPI) therapy for 3 months reduces asthma symptoms, and an esophageal pH study to detect silent GERD is recommended in those patients who experience uncontrolled asthma and/or nocturnal symptoms without GERD symptoms [31]. Patients with difficult-to-treat asthma should be investigated for GERD and offered empirical double-dose PPI therapy.

Metabolic syndrome

New interest is arising in the inflammatory mechanisms related to visceral obesity, insulin resistance and the metabolic syndrome in asthmatic patients. Obesity, particularly abdominal obesity, is the main component of the metabolic syndrome, which is associated with asthma-like symptoms [32]. Morbidly obese children and adolescent asthmatics have a higher degree of insulin resistance compared with morbidly obese nonasthmatic patients [33], provoking deliberation on the proinflammatory nature of insulin resistance in the etiopathogenesis of the obese asthmatic. It is very likely that the inflammatory nature of insulin resistance may be a contributory risk factor for asthma in obesity.

Diabetes mellitus

In hospitalized patients [34], diabetes mellitus is associated with statistically significant compromised pulmonary function [35]. Whether this finding is part of the metabolic association remains to be investigated along with the resulting clinical implications.

Mood disorders

Serious psychological distress is prevalent in 7.5% of adult asthmatics [36], inviting speculation that lifestyle factors influencing health-related quality of life provoke psychological distress and worsen asthma. Commonly, poorly controlled asthmatic patients are obese with poor pulmonary function and are also anxious and/or depressed [37]. Targeting early identification and management of mood disorders and anxiety in asthma can pre-empt the worsening of asthma symptoms.

Asthma & other chronic diseases

The common presence of GERD in systemic sclerosis with pulmonary fibrosis [38] and idiopathic pulmonary fibrosis [39] may lend explanation for the occurrence of asthma in these subgroups. Coexistent asthma with autoimmune conditions is supported by a positive correlation between uncontrolled asthma and plasma TGF-β1 [40], and clinical evidence of higher asthma frequency in inflammatory bowel disease [41].

In conclusion, the inflammatory nature of asthma is shared by many of its comorbid partners, whose role in the clinical expression of the disease remains to be elucidated. Asthma control as an aggregated outcome measure of disease severity, therapeutic intervention and treatment compliance is confounded by comorbidity. Influences from comorbid conditions are variable and uncertain, however, because they influence clinical burden, therapeutic response and disease management, their awareness should prompt systematic evaluation and treatment. Asthma control is, therefore, dependent on control of its comorbidity.

Financial & competing interests disclosure

Lexley Pinto Pereira has received research and travel grants from Astra Zeneca, GlaxoSmithKline, Boehringer Inglheim and Merck Sharpe and Dohme. Terence Seemungal has received travel grants from Astra Zeneca, GlaxoSmithKline and Boehringer Inglheim. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.