Performance of fractional exhaled nitric oxide in predicting response to inhaled corticosteroids in chronic cough: a meta-analysis

Figures & data

Table 1. Baseline demographic and clinical data of patients with chronic cough treated with inhaled corticosteroids (ICS) in included studies.

Study	High FeNO (n)	Low FeNO (n)	Males (%)	Age (years)	BMI (kg/m^2)	Smoking (%)	Recent RTI (%)	ACE-I (%)	Asthma (%)	Atopic status (%)	ICS naïve (%)	FEV1 (% predicted)	FEV1/FVC
Hahn 2007	41	23	40.6	46.8	28.9	15.6^b	–	0	48.4^c	–	–	95.6	–
Hsu 2013	43	1	47.7	49.1	–	0	–	–	0	–	–	90.2	81.4
Koskela 2013^a	15	24	25.5	55.6	27.4	0	0	–	20.9^d	32.6	–	93.7	–
Lamon 2019	41	22	38.1	59.2	25.7	30.1^b	–	–	9.5^e	12.7	–	95.7	72.8
Price 2018^a	31	65	47.4	50.0	27.6	9.6	0	0	54.8	–	–	90.8	78.0
Prieto 2009	19	24	43.4	48.0	–	0	0	0	9.3^c	100	100	113.2	81.9
Shebl 2020	41	29	41.4	46.7	30.1	0	–	–	–	–	–	86.2	88.9
Watanabe 2016	21	56	44.1	47.8	–	51.9	13.0	–	50.6	5.2	55.8	–	–
Yi 2016	139	105	53.7	39.8	–	0	0	–	28.3	54.7^f	–	96.0	80.4

Pop: population; BMI: body mass index; RTI: respiratory tract infection; ACE-I: angiotensin converting enzyme-inhibitors; FEV₁: forced expiratory volume in 1 s; FVC: forced vital capacity. Continuous data are expressed as mean values, unless otherwise indicated.

^aBaseline demographic and clinical data refer to an original population of 43 patients for Koskela 2013 and 114 patients for Price 2018.

^bAny smoking history (previous or current).

^cAsthma defined by methacholine challenge tests.

^dAsthma defined by questionnaires.

^eAsthma defined by positive anamnesis.

^fOnly 95 patients with available atopy data.

Table 2. Characteristics related to study design and inhaled corticosteroids (ICS) treatment in included studies.

Study	Study design	Definition of chronic cough	Cough duration	ICS type/dose	Follow-up	Definition of ICS response
Hahn 2007	Retrospective	≥8 weeks	40.3 months	Fluticasone propionate 434 μg/day	5.3 months	Physician-documented significant improvement in cough, no further diagnostic study ordered for assessment of cough, and no alteration in ICS dose
Hsu 2013	Retrospective	≥8 weeks	15.3 months	Fluticasone propionate 250 μg twice/day	≥2 weeks	Complete control of cough determined by physician
Koskela 2013	Prospective	≥8 weeks	8.5 years	Budesonide 400 μg twice/day	12 weeks	Improvement of > 1.3 points in the Leicester Cough Questionnaire score
Lamon 2019	Retrospective	≥8 weeks	43.1 months	Unspecified ICS 1,020 μg/day	≥3 months	Self-reported reduction of cough frequency
Price 2018	Double-blind randomised placebo-controlled trial	≥6 weeks	–	Beclomethasone dipropionate 800 μg/day	4 weeks	Improvement of ≥ 20 mm in the VAS cough score
Prieto 2009	Prospective	≥8 weeks	–	Fluticasone propionate 100 μg twice/day	4 weeks	Reduction of > 50% in the mean daily cough symptom scores
Shebl 2020	Prospective	≥8 weeks	–	–	4 weeks	Complete cough disappearance according to a cough symptom score^a
Watanabe 2016	Retrospective	≥3 weeks	15.4 months	–	3 months	Significant improvement in cough with ICS declared by the patient and confirmed by the physician
Yi 2016	Prospective	≥8 weeks	–	–	–	Complete control of cough determined by physician^b

LCQ: Leicester Cough Questionnaire; VAS: Visual Analogue Scale. Continuous data are expressed as mean values, unless otherwise indicated.

^aInformation from another reference by the same authors [41].

^bInformation from another reference by the same authors [42].

Figure 1. Quality of included studies according to Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) criteria.

Figure 2. Forest plots of cough response to inhaled corticosteroids in patients with high and low fractional exhaled nitric oxide (A) and of the mean difference in fractional exhaled nitric oxide between responders and non-responders (B). FeNO: fractional exhaled nitric oxide; 95%CI: 95% confidence interval. Squares represent the Odds Ratio of steroid response in chronic cough patients with a high and low FeNO in each study (A) or the Mean Difference in FeNO between responders and non-responders to corticosteroids. Lines are the 95% confidence intervals. The black diamond represents the cumulative Odds Ratio (A) or the cumulative Mean Difference (B) for analysed studies.

Figure 3. Pooled estimates of sensitivity and specificity for the association between high fractional exhaled nitric oxide (FeNO) and response to inhaled corticosteroids in chronic cough, with Fagan’s nomogram from pooled likelihood ratios. 95%CI: 95% confidence interval. Squares represent the sensitivity or specificity for the association between high FeNO and response to inhaled corticosteroids. Lines are the 95% confidence intervals.

Figure 4. Hierarchical Summary Receiver Operating Characteristic (HSROC) curve (A) and Deeks test for funnel plot asymmetry (B). HSROC_AUC: area under the HSROC curve; ESS: effective sample size.

Table 3. Pooled diagnostic indexes for the association between high fractional exhaled nitric oxide (FeNO) and response to inhaled corticosteroids in sensitivity and subgroup analyses.

	SENSITIVITY ANALYSES				SUBGROUP ANALYSES
	Exclusion of retrospective studies	Exclusion of data on smokers	Exclusion of studies not using the recommended ≥ 8-week limit for chronic cough definition	Exclusion of studies with high risk of bias and/or applicability concerns in patient selection	FeNO cut-off ≤ 25 ppb	FeNO cut-off > 25 ppb
Sensitivity (%)	54.3 (95%CI: 37.3–70.5)	64.2 (95%CI: 58.2–69.9)	76.0 (95%CI: 52.2–90.1)	79.2 (95%CI: 53.0–92.8)	49.6 (95%CI: 39.0–60.2)	77.4 (95%CI: 46.5–93.1)
Specificity (%)	83.6 (95%CI: 70.7–91.5)	83.4 (95%CI: 77.0–88.7)	78.1 (95%CI: 53.8–91.6)	73.9 (95%CI: 43.6–91.2)	79.7 (95%CI: 60.2–91.1)	81.3 (95%CI: 50.2–94.9)
PLR	3.31 (95%CI: 1.51–7.28)	2.55 (95%CI: 0.83–7.80)	3.47 (95%CI: 1.65–7.30)	3.04 (95%CI: 1.31–7.05)	2.44 (95%CI: 1.12–5.33)	4.14 (95%CI: 1.50–11.41)
NLR	0.55 (95%CI: 0.35–0.84)	0.36 (95%CI: 0.20–0.67)	0.31 (95%CI: 0.16–0.61)	0.28 (95%CI: 0.12–0.64)	0.63 (95%CI: 0.48–0.84)	0.28 (95%CI: 0.11–0.69)
HSROCAUC	0.77 (95%CI: 0.53–0.91)	0.78 (95%CI: 0.54–0.91)	0.83 (95%CI: 0.55–0.90)	0.82 (95%CI: 0.64–0.89)	0.52 (95%CI: 0.47–0.63)	0.83 (95%CI: 0.62–0.94)

PLR: positive likelihood ratio; NLR: negative likelihood ratio; SROC_AUC: area under the summary receiver operating characteristic curve; Q* index: intercept of the summary receiver operating characteristic curve; HSROC_AUC: area under the hierarchical summary receiver operating characteristic curve.

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Data availability statement

The data that support the findings of this study are available from the corresponding author [M.M.] upon reasonable request.