Narrative Review: how long should patients with cough variant asthma or non-asthmatic eosinophilic bronchitis be treated?

Abstract

The causes of chronic cough can be categorized into eosinophilic and noneosinophilic disorders, and approximately 30% to 50% of people with chronic cough have eosinophilic airway inflammation, the presence of which can be confirmed by sputum eosinophilia or elevated exhaled nitric-oxide levels. Cough variant asthma (CVA) is a phenotype of asthma which lacks wheezing or dyspnea, and consistently one of the most common causes of chronic cough worldwide. CVA and non-asthmatic eosinophilic bronchitis (NAEB) shares common feature such as chronic dry cough, eosinophilic inflammation, and development of chronic airflow obstruction (CAO) and asthma in a subset of patients. The distinctive characteristic of these conditions is the presence of airway hyperresponsiveness in CVA but not in NAEB. Coughing is responsive to bronchodilators such as beta-agonists in CVA, but such feature has not been clarified in NAEB. Inhaled corticosteroids (ICSs) are the first-line treatment, and leukotriene receptor antagonists are also effective, in patients with both CVA and NAEB. This review will give an outline of clinical and physiological features, and prognosis and its determinants of CVA and EBNA. Further, the rationale and evidence, despite limited, for the need of long-term treatment will be discussed. The development of airway remodeling due to mechanical stress to the airways exerted by long-standing coughing will also be discussed.

Keywords: Cough variant asthma (CVA); airway remodeling; chronic cough; eosinophilic airway inflammation; long-term treatment; non-asthmatic eosinophilic bronchitis (NAEB).

Figure 1

Prevalence of repeated seasonal exacerbations in each season in patients with classic asthma and CVA (16). A “seasonal” character of exacerbation was defined by at least one exacerbation in a specific season (spring, summer, autumn, and winter) repeatedly for least 2 years during the study period. Seasonal exacerbations as defined above was more common in CVA (18/23; 78%) than in classic asthma (18/38; 47%) (P=0.03), and CVA patients had seasonal exacerbations more frequently in autumn season than those with classic asthma (48% vs. 16%; P=0.009).

Figure 2

Prevalence of classic asthma and CVA patients in two novel phenotypes of asthma defined by the predominant cite of eosinophilic airway inflammation (19,22). By using early-phase (first-half 15 minutes) and late-phase (second-half 15 minutes) induced sputum, patients were divided into “larger airway eosinophil-predominant group” (early-phase eos% > late-phase eos%) and “smaller airway eosinophil-predominant group” (early-phase eos% < late-phase eos%). Ten (91%) of 11 CVA patients was categorized as larger airway eosinophil-predominant, while only half (12 of 24) of classic asthma patients had smaller airway-predominant inflammation (P=0.02). *eos: eosinophils.

Figure 3

Cough receptor sensitivity (CRS) as define by the threshold concentration of capsaicin to elicit at least 5 coughs (C5) in patients with asthma stratified by severity, defined by the need of maintenance oral corticosteroids (OCSs) (38). Patients with more severe asthma showed significantly heightened CRS as compared with non-severe asthmatics. *OCSs+, patients taking maintenance OCSs; OCSs-, patients not taking maintenance OCSs.

Figure 4

Maintenance ICS doses in CVA patients stratified by inflammatory subtype of sputum (61). *CVA, cough variant asthma; ICS, inhaled corticosteroids.

Figure 5

Histologic changes in (A) the BM thickness of tracheal and (B) the ASM index of small airways, in the three treatment groups of guinea pigs (saline, citric acid, and citric acid pretreated with codeine) after 3 weeks and 6 weeks (79). **P<0.01, *P<0.05 by one-way ANOVA, LSD post hoc test; ♦P<0.05 by Student’s t-test. BM, basement membrane; ASM, airway smooth muscle.

Figure 6

Correlation between the frequency of cough and (A) the tracheal BM thickness and (B) the ASM index of small airways after 6 weeks of CA exposure in guinea pigs (79). BM, basement membrane; ASM, airway smooth muscle; CA, citric acid.

Figure 7

Representative photomicrographs of airway sections in the three treatment groups after 6 weeks of exposure (79). (A) In the large airways, BM thickness is increased after 6 weeks of treatment in the CA group compared with the other two groups. (B) In the small airways, ASM is increased after 6 weeks in the CA group compared with the other two groups (hematoxylin and eosin, ×400). CA, citric acid; SA, saline solution; COD, citric acid with codeine pretreatment; BM, basement membrane; ASM, airway smooth muscle.