Cough-Variant Asthma: A Review of Clinical Characteristics, Diagnosis, and Pathophysiology

Abstract

Chronic cough is among the most common symptoms prompting medical care. Cough-variant asthma (CVA) is an asthma subset where cough is the primary symptom, without wheezing, chest tightness, or dyspnea. It is an important cause of chronic cough, estimated to account for 25% to 42% of cases, but likely underdiagnosed due to delayed recognition and pitfalls of diagnostic testing. Early recognition and treatment can reduce morbidity and delay its progression to more typical asthma. This review details the clinical characteristics, diagnosis, pathophysiology, and treatment of CVA and contrasts it with classic asthma and other causes of chronic cough.

Chronic cough, a cough lasting more than 8 weeks in adults or 4 weeks in children, is among the most common symptoms prompting medical care.¹ It affects nearly 10% of the worldwide population.² Asthma, upper airway cough syndrome (UACS), gastroesophageal reflux disease (GERD), and nonasthmatic eosinophilic bronchitis (NAEB) are common etiologies for chronic cough. Some patients have a combination of these underlying diseases, and asthma accounts for an estimated 25% of chronic cough.³

Cough-variant asthma (CVA) was described by Glauser⁴ in 1972 as a bronchodilator-responsive cough and a subset of asthma where cough is the primary symptom. The CVA label has expanded to encompass cough responding to asthma treatment in the absence of wheeze and variable airflow obstruction. It is estimated to account for 25% to 42% of chronic cough cases and is the most common reason for chronic cough in Japan and China and the second most in Europe and the United States.^5–8 Asthma can remain undiagnosed in 20% to 70% of patients,⁹ and CVA is likely further underdiagnosed due to delayed recognition because of the absence of other classic asthma (CA) symptoms, for example, wheezing, chest tightness, and dyspnea. The presence of other comorbidities that also cause cough, such as GERD and UACS, as well as pitfalls of diagnostic testing, also leads to delays in recognition of CVA as a cause of symptoms. The appropriate recognition and treatment of CVA can reduce the morbidity associated with chronic cough and perhaps decrease its progression to CA.^10,11 This review details the clinical characteristics, diagnosis, pathophysiology, and treatment of CVA and other causes of chronic cough.

CLINICAL FEATURES AND DIAGNOSIS

CVA presents as a paroxysmal cough without other symptoms of CA, that is, wheezing, chest tightness, and dyspnea, and like CA, it is triggered by exposure to various allergens, viral respiratory tract infections, cold air, environmental irritants, and other factors. As with other forms of asthma, CVA can be associated with other diseases, including GERD or chronic rhinitis.¹² When cough symptoms of patients with CVA versus those with CA are compared, CVA cough scores can be higher despite no differences in rates of these comorbidities.^13,14 Patients with CA generally have a longer duration of disease than those with CVA by 25 to 72 months.^13,15,16 Patients with CA are more likely to be allergic to a greater number of aeroallergens, particularly perennials, than patients with CVA, but their atopic status, defined as sensitization to at least one allergen, is identical.^16–18 CVA progresses to CA in 30% to 40% of patients.^10,11 Clinical features linked to CVA progression to CA include increased sputum eosinophilia,¹⁹ longer disease duration,²⁰ bronchial hyper-reactivity (BHR),^11,21 sensitization to a greater number of aeroallergens,¹⁶ and failure to use inhaled corticosteroids (ICS) early in treatment.^10,11

Symptoms of cough, dyspnea, chest tightness, and wheeze in CA are typically associated with variable expiratory airflow limitation in response to triggers, which can be demonstrated with appropriate pulmonary function tests. The Global Initiative for Asthma (GINA) report²² describes demonstration of any of the following as consistent with reversible airflow limitation: (1) demonstration of bronchodilator reversibility (BDR), defined as a forced expiratory volume in 1 second (FEV1) increase by at least 12% and 200 mL from baseline 15 minutes after administration of a bronchodilator; (2) a positive bronchial challenge test, defined as a fall in FEV1 of ≥20% with a standardized methacholine challenge or ≥15% with a mannitol challenge; (3) serial peak expiratory flow monitoring with a mean variability of >10% in adults or >13% in children; or (4) an improvement in FEV1 by at least 12% and 200 mL after 4 weeks of ICS treatment. European and Japanese Society guidelines are similar with the exception that they consider the peak flow variability of ≥20% to be diagnostic.^23,24 European guidelines also add an improvement in FEV1 by at least 12% and 200 mL after a 2-week course of oral corticosteroid. The European Respiratory Society (ERS) and the American Thoracic Society now recommend changes in FEV1 or forced vital capacity (FVC) >10% relative to the predicted value to define BDR.²⁵

Many patients with CVA do not demonstrate BDR, the most common initial test performed to confirm the diagnosis of CA.²⁶ One study indicates that up to one-third of patients with CVA do not have any bronchodilator response.²⁷ Spirometry in CVA is often normal and therefore not as helpful as in CA.^12,14,26 FEV1 is commonly significantly higher in CVA than CA.^13–15,28 Another study examined patients with CVA with negative BDR and found that most (73.8%) had a predicted FEV1 >80%, and all had predicted FEV1 ≥70%, with mean demonstrated FEV1/FVC 0.79.²⁹ The frequent lack of BDR in patients with CVA likely relates to normal lung function commonly found in patients with CVA because the demonstration of BDR is more challenging among patients with normal lung function.

Different diagnostic testing cutoffs may be needed to better identify CVA. Among patients with chronic cough without BDR, Hao et al²⁹ suggest a change in FEV1 of ≥5.9% as predictive of CVA and of responsiveness to ICS treatment (area under the curve [AUC]: 0.825). Measures of small airway function alone (forced expiratory flow between 25% and 75% of FVC [FEF25–75] predicted ≤61.99%) or combined with fractional excretion of nitric oxide (FeNO, ≥41.50 parts per billion [ppb]), both described elsewhere, also had predictive value in diagnosing BDR-negative patients with CVA (AUC: 0.714 and 0.762, respectively).

When reversibility is absent, a CVA diagnosis can be better supported by demonstrating BHR using bronchoprovocation testing, but these are more commonly performed in research settings and less commonly in clinical practice. Methacholine bronchoprovocation testing responses are quantified as the provocative methacholine concentration (PC20) or dose (PD20), which causes a 20% decline in FEV1. A PC20 ≤8 mg/mL and a PD20 ≤200 μg are considered positive.^23,30 Asthma diagnostic guidelines do not distinguish between CVA and CA in terms of PC20 or PD20 cutoffs. Comparison studies generally show lower PD20 in CA versus CVA.^{14,15,18,28,31}

Given that BDR is not always present in CVA, challenge testing is useful to rule out BHR because its absence rules out a CVA diagnosis. However, positive bronchoprovocation testing results are sensitive but not specific to asthma and are frequently found in patients with allergic rhinitis and cystic fibrosis, smokers, healthy individuals, and in other disorders.^32,33 Cough is also common in some of these populations. Demonstrating BHR with methacholine predicts a clinical response to ICS/long-acting β-agonist (LABA) therapy in 87.8% of patients suspected to have CVA.³⁴

FeNO is also used as a supportive tool to diagnose and manage asthma.³⁵ It is characterized by type 2 airway inflammation, and FeNO levels correlate with sputum eosinophilia, bronchoalveolar lavage (BAL) eosinophilia, BHR,^36,37 and response to ICS.^38–40 ERS and National Asthma Education and Prevention Program guidelines^23,41 recommend a cutoff of ≥50 ppb as being supportive of an asthma diagnosis in suspected patients in whom initial spirometry and BDR testing is inconclusive. The GINA report⁴² however recommends against FeNO as a sole diagnostic tool for asthma given that it is not elevated in some asthma phenotypes (eg, neutrophilic asthma) and can be elevated in conditions other than asthma (eg, NAEB, allergic rhinitis, and atopy). Conversely, FeNO is helpful in identifying patients who are at greater risk of asthma exacerbations and those who are likely to respond to ICS.

Low FeNO levels for CA do not exclude the diagnosis of CVA. FeNO determinations are typically lower in CVA versus CA.^14,17,43 Levels in adults range from 17 to 39 ppb in patients with CVA versus 40 to 60 ppb in patients with CA. One additional study demonstrates a mean FeNO of 25 ppb in patients with CVA.⁴⁴ Another estimates an optimal FeNO cutoff of 24.5 ppb to differentiate CVA from non-CVA chronic cough.⁴⁵ A meta-analysis of FeNO in a population of patients with CVA, with optimal cutoff values ranging between 30 and 40 ppb, demonstrates relatively high specificity (85%) with lower sensitivity (72%).⁴⁶ Using this sensitivity and specificity and estimates of CVA prevalence among patients with chronic cough referenced above (25%–42%), a calculated positive predictive value of FeNO would be 62% to 78% and a negative predictive value 81% to 90%.

A positive response to asthma therapy is also ideal to support the diagnosis of CVA and distinguish it from other conditions with positive bronchoprovocation testing or elevated FeNO. When there is a clinical suspicion of CVA and bronchoprovocation or FeNO testing is unavailable, an empiric treatment trial also can be initiated. CVA is most often responsive to ICS compared with other asthma medications, with treatments for CVA discussed in more detail below. Demonstrating BHR distinguishes CVA from NAEB because both are ICS-responsive conditions and is therefore important for diagnostic and research purposes. Otherwise, demonstrating BHR does not delineate a unique treatment approach. See Figure 1 for additional details on diagnostic steps for CVA and Table I for distinguishing features between CVA, CA, and NAEB.

FIGURE 1.

Diagnostic algorithm for CVA.

TABLE I.

Overlap in clinical characteristics between cough-variant asthma, classic asthma, and nonasthmatic eosinophilic bronchitis

Clinical characteristic	Cough-variant asthma	Classic asthma	Nonasthmatic eosinophilic bronchitis
Cough	+	+	+
Dyspnea, wheeze	−	+	−
BDR/BHR	+	+	−
Airway eosinophilia	Typical	Typical	+
Airway remodeling	+	+	+
CRS	+	+	+
Response to ICS	+	+	+
Response to β-agonist	Poor	+	Poor

+, present; −, absent.BDR, Bronchodilator reversibility; BHR, bronchial hyper-reactivity; CRS, cough reflex sensitivity; ICS, inhaled corticosteroid.

In summary, there are no universal criteria to diagnose CVA. The diagnosis of CVA is based on a clinical assessment, appropriate diagnostic studies, and response to therapy. Based on the above information, CVA is best defined by (1) a predominant symptom of paroxysmal coughing, often in response to typical asthma triggers, however, without other asthma symptoms such as dyspnea, wheezing, and chest tightness; (2) evidence of variable expiratory airflow limitation, most often with BHR; and (3) therapeutic response primarily with ICS or bronchodilators.

PATHOPHYSIOLOGY AND COMPARISON WITH CA

The pathophysiology of CA and CVA involves similar mechanisms, cells, and mediators, and it is unclear how they result in different clinical presentations. The cough, wheeze, and dyspnea associated with CA are thought to result from BHR and eosinophilic airway inflammation, where persistent inflammation leads to airway remodeling and results in BHR. But BHR alone may not fully explain the pathobiology of CVA because the cough does not uniformly respond to bronchodilator therapy and is not associated with wheezing and dyspnea. Despite relatively preserved baseline lung function, some patients with CVA also have a more bothersome cough than patients with CA. Several studies examined the differences between CA and CVA in degrees of airway remodeling, small airway changes, airway inflammation, and airway nerve dysfunction.

Airway inflammation

Many patients with asthma, including CVA, exhibit eosinophilic airway inflammation. Airway eosinophilia is measured through induced sputum, BAL fluid, endobronchial biopsy specimens, or indirectly through FeNO. The degree of airway eosinophilia in CVA correlates with clinical severity scores and response to therapy.⁴⁷ BAL and sputum eosinophils, Th2 cytokines, and FeNO levels are more elevated in CA versus CVA.^{14,15,17,28,43,44} FEV1 correlated negatively with eosinophilia (r = −0.263, P = .002) and Th2 cytokines (IL-4 r = −0.261, P = .002; IL-5 r = e0.282, P = .001; IL-13 r = −0.251, P = .004).⁴³ Sputum eosinophil levels correlate with PD20 in CA and CVA, but this association is inconsistent across studies.^14,15 Greater sputum eosinophil levels are also a risk factor for progression of CVA to CA, as indicated above: sputum eosinophil % ≤2.4%, relative risk (RR): 1.55; 2.5% to 4.7%, RR: 2.13; 4.8% to 8.2%, RR: 3.75.¹⁹

Higher levels of eosinophilic airway inflammation do not alone predict severity of symptoms, and treatment with ICS does not always completely resolve symptoms in CA or CVA. Treatment of CA with mepolizumab, an IL-5 antagonist and potent inhibitor of eosinophilic inflammation, does not change BHR^48,49 or subjective cough⁵⁰ despite causing marked decreases in eosinophilia. A 2020 systematic review⁵¹ of multiple biologics in patients with severe CA found that changes in asthma control (assessed by questionnaire), quality of life measures, and FEV1 did not reach the minimally important difference (ie, the smallest improvement considered worthwhile to the patient). Biologics have not been systematically studied for CVA. However, these results suggest that CVA symptoms are likely related to factors other than just eosinophilic airway inflammation.

Not all asthma displays eosinophilic predominant airway inflammation. Non-eosinophil predominant phenotypes contribute to asthma severity. For example, neutrophilic and mixed granulocytic (ie, mixed eosinophilic and neutrophilic sputum) subtypes are associated with poor responses to treatment in moderate to severe asthma.^52–54 In one study, sputum neutrophil and eosinophil counts were both associated with a lower prebronchodilator FEV1, whereas only sputum total neutrophil counts were associated with a lower post-bronchodilator FEV1, indicating a possible role of neutrophilic airway inflammation in progression of persistent limitations in airflow.⁵⁵ In contrast, paucigranulocytic sputum (low levels of eosinophils and neutrophils in sputum) is frequently identified in patients with well-controlled asthma.⁵⁶

Studies have examined cellular phenotypes in treatment naïve CVA. The paucigranulocytic phenotype is estimated at 28% to 52% of patients, the eosinophilic phenotype at 29% to 33%, the neutrophilic phenotype at 15% to 32%, and the mixed granulocytic phenotype at 0% to 12%.^57,58 Studies in patients with CA show that paucigranulocytic (31%–52%) and eosinophilic (17%–42%) subtypes are the most common, followed by neutrophilic (16%–28%), then mixed granulocytic (3%–8%).^59–61 These estimates are not clearly different from CVA.

Inflammatory cell phenotypic subsets in CVA are not associated with differences in comorbidities (eg, GERD, atopy, smoking status, body mass index [BMI], UACS), BHR, or duration of disease. The neutrophilic subtype might be associated with decreased treatment responses.

Cluster analysis is used to characterize CVA phenotypes⁶² in terms of clinical characteristics, spirometry, sputum cellularity, and gene expression. Three clusters have been identified: (1) female predominant, late-onset disease with preserved lung function; (2) younger patients with high type 2 inflammation, atopy, and BHR; and (3) high BMI, long duration of illness, family history of asthma, and lowest baseline spirometry. Clusters 1 and 3 are characterized by higher sputum neutrophils and Th17 cell differentiation. Cluster 2 has the highest proportion of respondents to ICS treatment with complete resolution of cough (73.3%), followed by cluster 1 (60.8%), then cluster 3 (54.1%).

Mast cells are implicated in the pathobiology of both CA and CVA. Mast cells release cough-provoking mediators such as histamine and cysteinyl leukotrienes in addition to growth factors that contribute to airway smooth muscle (ASM) hypertrophy and BHR.⁶³ Patients with CA and CVA have increased mast cell infiltration of their ASM compared with other conditions, such as NAEB, where ASM infiltration by mast cells is lacking. Greater mast cell infiltration within ASM relates to greater BHR.^64,65 ICS reduce inflammation and airway mast cell numbers.^66,67 Although it would be expected that patients with CVA have less mast cell ASM infiltration, comparison studies comparing mast cell numbers and function in CVA versus CA have not been performed.

Sputum metabolic signatures may distinguish patients with CVA from healthy controls, as well as treatment responsiveness, but these results need to be validated in larger, prospective, and multicenter studies.⁶⁸

Airway remodeling

Airway structural changes, including bronchial wall thickening, goblet cell hyperplasia, subepithelial basement membrane thickening, and ASM hyperplasia, are characteristic of CA and termed airway remodeling. Such changes also have been demonstrated in CVA.^69,70 The mean subepithelial thickness determined from bronchial biopsy specimens was found to be significantly higher in CA (8.6 μm) versus CVA (7.1 μm), both of which were significantly higher than in controls (5.0 μm).⁷⁰ CVA versus healthy controls and nonasthmatic patients with chronic cough have increased airway wall thickness, as assessed by computed tomography (CT) scanning.⁶⁹ Another study, which assessed mucin levels in induced sputum (a proxy for goblet cell hyperplasia), found that patients with CA have greater mucin levels (674.2 μg/mL) than patients with CVA (350.4 μg/mL). Patients with CVA did not have significantly greater mucin levels than controls (212.0 μg/mL).⁷¹ Repetitive mechanical stress from bronchoconstriction alone is linked to airway remodeling, without a concomitant increase in inflammation,^72,73 and is thought to contribute to the remodeling seen in both CA and CVA. Lower levels of inflammation and less BHR in CVA versus CA likely contribute to decreased airway remodeling.

Remodeling in asthma can affect both the large and small airways, with small airways being defined as <2 mm in internal diameter.⁷⁴ Small airway remodeling contributes to small airway dysfunction (SAD), which is difficult to assess. Small airways are below resolution attained even with high-resolution CT (HRCT) scanning but can be inferred by the degree of air trapping or mosaicism findings, which is a patchwork of regions of differing attenuation.⁷⁴ Spirometry changes in FEF25–75, forced expiratory flow at 50% of FVC (FEF50), or changes in residual volume are also proposed as a way of measuring small airway function.⁷⁴

SAD in CA is associated with more severe symptoms, as well as markers of eosinophilia and BHR.^75–79 Although the prevalence of SAD is similar between CA and CVA (50%–60% and 45%–60%, respectively),^80–82 the severity of SAD, as determined by FEF25–75 and FEF50 measurements, seems to be greater in CA than CVA.^83,84 Yi et al⁸⁰ prospectively compared patients with CVA with and without SAD over 1 year and found that SAD was associated with a lower FEV1 and PD20 as well as longer cough duration, but without differences in sputum eosinophil levels, FeNO, or cough scores. Patients with SAD versus those without trended toward having higher rates of the development of wheeze and therefore CA. These rates did not reach statistical significance (10.4% vs 0%, P = .063), likely due to a small sample size and insufficient duration of follow-up. The authors speculate that SAD may be a marker for progression to CA. Yuan et al⁸¹ showed no differences in sputum eosinophil counts, cough scores, or differences in FEV1 in patients with CVA with SAD versus those without, and evidence of SAD persisted after initiation of antiasthmatic treatment, despite improvements in cough symptoms.

Cough reflex sensitivity

Cough is part of a natural defensive mechanism that helps prevent aspiration of harmful chemicals and foreign substances. In patients with chronic cough, including CVA, this normal response can be dysregulated, resulting in increased neuronal sensitivity and enhanced responses to cough-provoking substances.⁸⁵ Analogous to chronic pain, this is termed central sensitization, a process by which the central nervous system undergoes changes that alter the usual processing of and response to sensory stimuli. This results in the nervous system becoming hypersensitive to sensory input. Successful treatment of cough by neurotropic medications such as gabapentin and amitriptyline supports a neuropathic mechanism to chronic cough. This central sensitization is typically termed cough reflex sensitivity (CRS) in the asthma literature; it is a feature in CA and CVA.

CRS is measured as responses to capsaicin, a substance that triggers cough by acting on the transient receptor potential vanilloid 1 receptor, common to both airway nociceptors and mechanosensors.⁸⁶ Aerosolized capsaicin is delivered to patients in increasing concentrations, and the lowest concentration that provokes 2 (C2) or 5 coughs (C5) is recorded. CRS is characterized by increased sensitivity to capsaicin and thus lower C2/C5 levels.

Patients with CA and CVA typically have a lower threshold for capsaicin-induced cough relative to healthy controls. CRS can be unrelated to BHR, FeNO, eosinophil counts, FEV1, or ICS treatment,⁸⁷ supportive of a mechanism of CRS independent from other CA features. CRS is associated with poor asthma control and risk of exacerbation in CA.^88,89 Patients with CVA typically also have increased CRS.^13,90–93 Only a few studies have compared CRS levels in CVA versus CA. One study found lower C5 (ie, more severe CRS) in CVA versus CA (logC5 1.5 vs 2.5, P < .001),¹³ which correlated with cough severity questionnaire scores (r = 0.416, P < .001). However, other studies found no differences in C5 scores between CA and CVA.⁹³

The proposed pathobiologic mechanisms of CRS may involve blockage of normal inhibitory neural pathways⁹⁴ and inflammation causing sensitization of receptors as well as central neuroplasticity.⁹⁵ But inflammation alone seems unlikely to explain CRS given the lack of a relationship between markers of type 2 inflammation and CRS noted in studies.^13,87 Exposure of patients with CA to known allergens increases sputum eosinophilia and histamine sensitivity without changes in CRS.⁹⁶ ICS treatment also does not reliably improve CRS in patients with CA^89,97 or CVA.⁹⁸

Airway remodeling also correlates with CRS,^69,99 and there is evidence of increased airway nerve density secondary to remodeling.^100,101 Nerve dysfunction therefore could be a characteristic or a consequence of airway remodeling. Airway remodeling may also result from cough itself irrespective of its cause. For example, some studies note that mechanical perturbation from cough may contribute to release of epithelial and nerve growth factors, which contribute to remodeling, as well as upregulation of TRPV1, the capsaicin receptor.^99,102 Airway inflammation may also be related to trauma from coughing.¹⁰³ One longitudinal study of patients with unexplained chronic cough without asthma also showed an increased rate of FEV1 decline with a few also developing chronic airway obstruction.¹⁰⁴ This evidence suggests that increased cough from CRS could contribute to airway remodeling and airway inflammation, which then feeds back to generate greater CRS as a vicious cycle in both CA and CVA. Mechanistic studies on the development of CRS in CVA are lacking and are a target for future research.

NAEB: PART OF A CLINICAL SPECTRUM?

Patients with NAEB are also characterized by a chronic, nonproductive cough, eosinophilic inflammation, and risk of progression to CA, as in CVA. Patients with NAEB share several clinical and pathological similarities to CVA, and a comparison is presented below.

Prevalence estimates of NAEB among patients with chronic cough range from 10% to 30%.^105–107 They exhibit eosinophilic airway inflammation by definition. The absence of BHR, however, characterizes NAEB and distinguishes it from CA and CVA.^95,108–111 NAEB, as with asthma, is related to certain occupational exposures, such as flour,¹¹² isocyanates,¹¹² and acrylates.¹¹³ Atopy is also frequently present in NAEB, with estimates in the literature ranging from 20% to 70%.^18,114 Airway remodeling changes also have been demonstrated in NAEB.^64,114 For example, one HRCT study demonstrated significantly greater airway wall thickness in CA than in NAEB.¹¹⁵ Although mast cells are present in the airways of both conditions, mast cells in NAEB are more superficial and do not infiltrate ASM as they do in CA. Degree of ASM mast cell infiltration correlates with BHR changes in CA.⁶⁴

The natural history of NAEB is not fully understood. One cohort of patients with NAEB followed for 1 year demonstrated that 13% go on to develop asthma.¹¹⁶ An additional prospective study followed patients with NAEB for up to 4 years.¹¹⁷ ICS was used until resolution of cough symptoms, with most (75%) experiencing resolution at 2 months and the remainder within 4 months of the initiation of ICS therapy. Twenty-one percent had a recurrence of symptoms within 4 to 6 months. Drops in FEV1 and even the development of asthma were demonstrated among the subset with recurrent episodes. It was concluded that repeated NAEB episodes can be associated with the development of airway obstruction.

Diagnostic criteria for NAEB require demonstration of airway eosinophilia, which is not widely available. Empiric ICS treatment is therefore recommended by expert groups if NAEB is suspected.¹⁰⁵ Bronchodilators are often ineffective, similar to CVA.^108–111 CRS may also be increased in NAEB; however, it improves with treatment with ICS in contrast with CA.¹¹⁸ Table I shows areas of overlap between CVA, CA, and NAEB.

TREATMENTS

Inhaled glucocorticosteroids and β-agonists

CHEST and ERS guidelines both recommend ICS as first-line treatment for CVA.^105,119 ICS target the underlying type 2 inflammation, and multiple studies show a benefit for CVA.^120–127 ICS/LABA is effective in CVA when used as part of maintenance and reliever therapy.¹²⁷ Time to improvement in cough was not significantly different between moderate and high ICS doses in a study of patients with CVA, consistent with the flattening of the dose-response curve known for the treatment of CA with ICS.¹²⁴ However, ICS treatment in CVA results in greater improvements in BHR and inflammation compared with CA.¹²³ ICS effectiveness in CVA may depend on particle size. Sugawara et al¹²⁶ studied patients with CVA using impulse oscillometry, dividing patients into central (without SAD) and peripheral (with SAD) predominant types. There were no differences in patient characteristics, spirometry, or pretreatment cough scores between groups. Coarse particle ICS (fluticasone) was most effective for cough in central type patients. Fine particle ICS (mometasone) was most effective in the peripheral type. Moderate particle ICS (budesonide) was effective in both groups.

CVA can be unresponsive to short-acting bronchodilator monotherapy, as suggested previously by the lack of uniform BDR.^{12,27,128,129} One study demonstrated no change in cough in 80% of patients with CVA treated with a β-agonist alone.¹²⁰ Studies in CVA do show additive benefit of ICS/LABA inhalers versus ICS alone in improving or resolving cough.¹²²

Leukotriene receptor antagonists

Cysteinyl leukotrienes contribute to bronchial inflammation, bronchoconstriction, and airway remodeling in asthma. Sputum levels of cysteinyl leukotrienes are elevated in patients with CA.^63,130 They are produced primarily by eosinophils and mast cells in the lungs.¹³¹ The 2020 ACCP guidelines recommend leukotriene receptor antagonist (LTRA) as a second-line therapy after ICS in patients with CVA¹⁰⁵ based on multiple studies showing benefit.^132–136 LTRA improved cough and reduced CRS severity (logC5 increased from 1.2 to 2.2) despite no measured improvements in respiratory function.^{130,132,134,136,137} A higher proportion of mast cells on bronchial biopsy identify montelukast responders versus nonresponders.¹³⁸ LTRAs are most likely effective via their effects on mast cells and on eosinophilic inflammation and may have efficacy through independent effects on CRS.

Muscarinic antagonists

Tiotropium, a long-acting muscarinic antagonist (LAMA), is indicated as a step-up therapy for asthma symptoms refractory to ICS/LABA therapy. LAMAs increase airway caliber and reduce mucus secretions. Improvement of cough symptoms with tiotropium correlates with CRS improvement, not changes in FEV1, in at least 2 trials of patients with CA with chronic cough refractory to ICS/LABA.^139,140 The authors conclude that tiotropium may alleviate symptoms by improving mechanisms that target CRS, rather than through effects on ASM. Another study on a guinea pig model of chronic cough shows improvement of cough with tiotropium via a mechanism on airway nerves via TRPV1.¹⁴¹ Because the muscarinic antagonists glycopyrrolate and atropine did not show similar responses, the mechanism of improvement with tiotropium is unclear but seems unrelated to antimuscarinic effects on ASM.¹⁰⁵ Additional studies on the use of LAMA for treatment for CVA are needed.

CONCLUSIONS

CVA is a common contributor to chronic cough and is defined as (1) predominant symptom of paroxysmal coughing, often in response to typical asthma triggers, in the absence of other typical asthma symptoms such as dyspnea, chest pain, and wheeze; (2) evidence of variable expiratory airflow limitation, most often with BHR; and (3) decrease in symptoms with treatment with ICS or bronchodilators.

Patients with CVA versus CA are more likely to have a shorter duration of illness; fewer aeroallergen sensitizations, in particular to perennial aeroallergens; lower levels of airway eosinophilia and FeNO; milder airway remodeling; higher baseline FEV1 and PC20; and less robust responses to treatment with bronchodilators. Cough might be more bothersome in patients with CVA versus CA. They have similar comorbidities that contribute to cough such as chronic rhinitis and GERD. There is an increased rate of CRS among patients with CVA, which may be an independent mechanism explaining their disease. NAEB has many similarities to CVA but lacks BHR and may represent an early stage in the asthma clinical spectrum. Clinical features linked to CVA progression to CA include increased sputum eosinophilia, longer disease duration, increased BHR, sensitization to a greater number of aeroallergens, and failure to use ICS early in the treatment of CVA.

CVA often presents without obstruction on spirometry and lacks BDR in one-third of patients. A bronchoprovocation test to demonstrate BHR is ideal but not readily available. FeNO is also helpful to identify corticosteroid responsive asthma but is also not universally available. This represents a possible barrier to properly diagnosing and prescribing treatment. NAEB is most likely under-recognized because the diagnostic criterion required, that is, demonstration of airway eosinophilia, is not universally available. A high clinical index of suspicion is necessary.

Expert groups recommend ICS as first-line treatment for CVA with LTRA as a second-line therapy. Delay in ICS treatment is a risk factor for progression to CA. Inadequate ICS treatment is also a risk factor for progression of NAEB to CA. CRS and the resultant increase in cough, as noted above, may also be independent risk factors for airway remodeling and decreases in FEV1. Early recognition of disease and appropriate treatment are important to prevent morbidity. For example, ICS attenuates CRS in patients with NAEB, in contrast to CA and CVA. Given the benefits of early intervention and diagnostic challenges, an empiric 4-week trial of ICS should be considered in patients with refractory chronic cough when clinical suspicion is high. Finally, clinicians should monitor patients with CVA for the potential progression to CA.

Abbreviations used

ASM

Airway smooth muscle

AUC

Area under the curve

BAL

Bronchoalveolar lavage

BDR

Bronchodilator reversibility

BHR

Bronchial hyper-reactivity

BMI

Body mass index

C2

Concentration of capsaicin provoking 2 coughs

C5

Concentration of capsaicin provoking 5 coughs

CA

Classic asthma

CRS

Cough reflex sensitivity

CT

Computed tomography

CVA

Cough-variant asthma

ERS

European Respiratory Society

FeNO

Fractional excretion of nitric oxide

FEV1

Forced expiratory volume in 1 second

FEF25-75

Forced expiratory flow between 25% and 75% of forced vital capacity

FEF50%

Forced expiratory flow at 50% of FVC

FVC

Forced vital capacity

GERD

Gastroesophageal reflux disease

GINA

Global Initiative for Asthma

HRCT

high-resolution CT

ICS

Inhaled corticosteroid

LABA

Long-acting β-agonist

LAMA

Long-acting muscarinic antagonist

LTRA

Leukotriene receptor antagonist

NAEB

Nonasthmatic eosinophilic bronchitis

PC20

Provocative concentration of methacholine causing a 20% decline in FEV1

PD20

Provocative dose of methacholine causing a 20% decline in FEV1

ppb

Parts per billion

SAD

Small airway dysfunction

UACS

Upper airway cough syndrome