Allergy Asthma Immunol Res.  2019 Nov;11(6):830-845. 10.4168/aair.2019.11.6.830.

Value of Exhaled Nitric Oxide and FEF(25–75) in Identifying Factors Associated With Chronic Cough in Allergic Rhinitis

• Liu X
• Wang X
• Yao X
• Wang Y
• Sun Y
• Zhang L

• KMID: 2459187
• DOI: http://doi.org/10.4168/aair.2019.11.6.830

Abstract

PURPOSE
Chronic cough in allergic rhinitis (AR) patients is common with multiple etiologies including cough variant asthma (CVA), non-asthmatic eosinophilic bronchitis (NAEB), gastroesophageal reflux-related cough (GERC), and upper airway cough syndrome (UACS). Practical indicators that distinguish these categories are lacking. We aimed to explore the diagnostic value of the fraction of exhaled nitric oxide (FeNO) and forced expiratory flow at 25% and 75% of pulmonary volume (FEF(25-75)) in specifically identifying CVA and NAEB in these patients.
METHODS
Consecutive AR patients with chronic cough were screened and underwent induced sputum, FeNO, nasal nitric oxide, spirometry, and methacholine bronchial provocation testing. All patients also completed gastroesophageal reflux disease questionnaires.
RESULTS
Among 1,680 AR patients, 324 (19.3%) were identified with chronic cough, of whom 316 (97.5%) underwent etiology analyses. Overall, 87 (27.5%) patients had chronic cough caused by NAEB, 78 (24.7%) by CVA, 16 (5.1%) by GERC, and 81 (25.6%) by UACS. Patients with either NAEB or CVA (n = 165, in total) were further assigned to a common group designated as CVA/NAEB, because they both responded to corticosteroid therapy. Receiver operating characteristic curves of FeNO revealed obvious differences among CVA, NAEB, and CVA/NAEB (area under the curve = 0.855, 0.699, and 0.923, respectively). The cutoff values of FeNO at 43.5 and 32.5 ppb were shown to best differentiate CVA and CVA/NAEB, respectively. FEF(25-75) was significantly lower in patients with CVA than in those with other causes. A FEF(25-75) value of 74.6% showed good sensitivity and specificity for identifying patients with CVA.
CONCLUSIONS
NAEB, CVA, and UACS are common causes of chronic cough in patients with AR. FeNO can first be used to discriminate patients with CVA/NAEB, then FEF(25-75) (or combined with FeNO) can further discriminate patients with CVA from those with CVA/NAEB.

Keyword

Chronic cough; allergic rhinitis; asthma; eosinophilic bronchitis; FeNO; FEF(25–75) percent

MeSH Terms

Asthma
Bronchial Provocation Tests
Bronchitis
Cough*
Eosinophils
Gastroesophageal Reflux
Humans
Methacholine Chloride
Nitric Oxide*
Rhinitis, Allergic*
ROC Curve
Sensitivity and Specificity
Spirometry
Sputum
Methacholine Chloride
Nitric Oxide

Figure

• 

  Fig. 1 Schematic diagram of the screening and diagnostic protocol used for chronic cough in AR patients. AR, allergic rhinitis; BDT, bronchial dilation test; BPT, bronchial provocation test; CVA, cough variant asthma; Eos, Eosinophils; FEF25–75: forced expiratory flow at 25% and 75% of pulmonary volume; FeNO, fraction of exhaled nitric oxide; FEV1, forced expiratory volume in 1 second; GERC, gastroesophageal reflux-related cough; GERD, gastroesophageal reflux disease; GerdQ, gastroesophageal reflux disease questionnaire; ICS, inhaled corticosteroids; INCS, intranasal corticosteroids; LABA, long-acting beta2-agonist; NAEB, non-asthmatic eosinophilic bronchitis; nNO, nasal nitric oxide; PPI, proton pump inhibitor; UACS, upper airway cough syndrome; VAS, visual analogue scales; IgE, immunoglobulin E. *If FEV1 ≥ 70% predicted value, then conducted BPT; otherwise conducted BDT. †Etiological treatment: CVA, ICS plus bronchodilators (budesonide/formoterol, 320/9 µg bid 4 weeks, then reduced to 160/4.5 µg bid for at least 4 weeks at the relief of symptoms); NAEB, ICS (budesonide, 400 mg bid for 8 weeks); GERC, 1) lifestyle modification (losing weight; avoiding snacks at night, acidic drink, coffee, alcohol, chocolate, oily foods, and so forth) and 2) PPI (omeprazole, 20 mg bid). All the above treatments continued for at least 12 weeks; UACS, INCS (budesonide, 128 mg bid for 12 weeks) and second-generation antihistamine po (loratadine, 10 mg daily for 4 weeks). ‡Besides the etiological treatment for CVA, NAEB, GERC and the managements for GERC, all chronic cough patients received targeted therapy for AR.

• 

  Fig. 2 Comparisons of induced sputum Eos (%) (A), FeNO (ppb) (B), nNO (ppb) (C), FEV1 (D), and FEF25–75 (E) among the different groups. NS, not significant; AR-only, allergic rhinitis patients without chronic cough; CVA, cough variant asthma; Eos, Eosinophils; FEF25–75, forced expiratory flow at 25% and 75% of pulmonary volume; FeNO, fraction of exhaled nitric oxide; FEV1, forced expiratory volume in 1 second; GERC, gastroesophageal reflux-related cough; NAEB, non-asthmatic eosinophilic bronchitis; UACS, upper airway cough syndrome; nNO, nasal nitric oxide. *Statistical significance at P < 0.05; †Statistical significance at P < 0.01.

• 

  Fig. 3 Correlation of FeNO (ppb) with induced sputum Eos (%) (A), nNO (ppb) (B), FEV1 (C), and FEF25–75 (D). Pearson correlation coefficients were used for expressing the correlations. Eos, Eosinophils; FEF25–75: forced expiratory flow at 25% and 75% of pulmonary volume; FeNO, fraction of exhaled nitric oxide; FEV1, forced expiratory volume in 1 second; nNO, nasal nitric oxide.

• 

  Fig. 4 ROC curves of FeNO, nNO, FEV1, and FEF25–75 for assessing diagnostic accuracy. ROC curves of FeNO and nNO for assessing the diagnostic accuracy for CVA (A), NAEB (B), CVA/NAEB (C), ROC curves of FeNO and nNO for assessing the diagnostic accuracy for NAEB in chronic cough without CVA (D), FEV1 and FEF25–75 for assessing the diagnostic accuracy for CVA in all chronic cough patients (E), for CVA only in CVA/NAEB patients (F), and FeNO model, FEF25–75 model, and combined model for assessing the diagnostic accuracy for CVA (G). ROC, receiver operating characteristic; CVA, cough variant asthma; CVA/NAEB, either NAEB or CVA; FEF25–75, forced expiratory flow at 25% and 75% of pulmonary volume; FeNO, fraction of exhaled nitric oxide; FEV1, forced expiratory volume in 1 second; NAEB, non-asthmatic eosinophilic bronchitis; nNO, nasal nitric oxide.

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