Clinical utility of asthma biomarkers: from bench to bedside

Figures & data

Figure 1 Asthma biomarkers.

Abbreviations: BAL, bronchoalveolar lavage; ECP, eosinophil cationic protein; FeNO, fraction of exhaled nitric oxide; IgE, immunoglobulin E; uLTE4, urinary leukotriene E4.

Figure 2 Inflammatory phenotypes of adult asthma patients obtained by sputum induction. (A) Eosinophilic type; marked by the presence of eosinophils ≥3% (red arrow). The hollow arrow indicates an alveolar macrophage. (B) Neutrophilic type; marked by the presence of neutrophils (blue arrow) ≥61%. The hollow arrow indicates an alveolar macrophage. (C) Mixed type; marked by the presence of both eosinophils (red arrow) ≥3% and neutrophils (blue arrow) ≥61%. (D) Paucigranulocytic type; marked by a lack of eosinophils (<3%) and neutrophils (<61%). The arrow shows a ciliated pseudostratified columnar airway epithelial cell (black arrow), a neutrophil with phagocytosed bacteria inside (blue arrow) and an alveolar macrophage (hollow arrow). May-Grünwald/Giemsa staining, photograph at 100× magnification, courtesy of Dr JAM van der Linden (UMC Utrecht, The Netherlands).

Table 1 Studies that assessed the association between fraction of FeNO and asthma control

	Study population	Study design	NO device	Asthma control	Outcome	Evidence for association
Vijverberg et al^Citation101	601 children (age: 4–12 yrs) with a reported use of asthma medication	Cross-sectional	NIOX Mino	ACQ-6	Weak positive correlation between FeNO and ACQ score (Rs = 0.13, P = 0.002), but poor accuracy to discriminate poor from well-controlled asthma (AUC: 0.56, 95% CI: 0.52–0.61, P = 0.008).	+/−
Ozier et al^Citation104	90 adults with asthma	Prospective follow-up of 3 wks for controlled patients and 3–6 months for uncontrolled patients	EndoNO, NIOX Mino	ACQ-6	No correlation between FeNO measurements and ACQ scores. PPV of FeNO < 50% to predict uncontrolled asthma. FeNO had a high NPV to predict loss of control in already controlled patients (>95%).	+/−
Mahut et al ^Citation102	200 asthmatic patients (107 children and 93 adults)	Prospective, 12 weeks of follow-up	ENDONO 8000	7-item and 6-item ACQ	FeNO did not correlate with ACQ at inclusion or during follow-up.	−
Sardón-Prado et al^Citation103	268 asthmatic children (age: 7–14 yrs)	Cross-sectional	NIOX Mino	CAN questionnaire	Weak correlation between FeNO and asthma control (r = 0.2).	+/−
Pérez-de-Llano et al^Citation105	102 adults with suboptimal asthma control	Prospective	NIOX Mino	ACT	FeNO had a PPV of 87.5% and a NPV of 90.6% to predict asthma control.	+
Shirai et al^Citation106	105 asthmatic patients	Cross-sectional	Sievers NOA 280i	ACT	Weak correlation between FeNO and asthma control (r =-0.3 1, P = 0.003).	+/−
Khalili et al^Citation107	100 asthma patients (age: 6–86 yrs)	Cross-sectional	NIOX	ACT, ACQ, NAEPP goals of therapy, JTFPP on attaining optimal asthma control, GINA guidelines	No significant association was found between FeNO level and asthma control based on ACQ (P > 0.99), ACT (P = 0.53), NAEPP (P = 0.53), JTFPP (P = 0.30), or GINA (P = 0.86) criteria.	−
Michils et al^Citation108	341 adults with asthma	Prospective with post hoc data analysis	LR 2000	ACQ-6	FeNO is a good marker of asthma control over time (especially in patients with low doses of ICS). FeNO decrease <40% or increase <30% precludes asthma control optimization or deterioration, (NPV: 79% and 82%, respectively). In the low-dose ICS group, a decrease >40% indicated control optimization (PPV: 83%).	+
Senna et al^Citation109	27 newly diagnosed asthma patients (age: 16–57 yrs)	Cross-sectional	CLD 88 sp	ACT	Good correlation between ACT score and FeNO (r =0.7, P = 0.001).	+
Robroeks et al^Citation110	64 asthmatic children (5–16 yrs)	Cross-sectional	NIOX	Based on GINA	FeNO was associated with poor asthma control, but the association was strongest when FeNO was combined with markers in exhaled breath condensate (AUC 0.761, P < 0.001).	+/−
Rosias et al^Citation111	23 children with mild to moderate asthma (age: 6–16 yrs)	Cross-sectional	NIOX	ACQ	No significant correlation between FeNO and ACQ (r = 0.48, P = 0.06).	−
Strunk et al^Citation112	144 children with mild to moderate persistent asthma (age: 6–17 yrs)	Cross-over RCT ICS/LTRA	NIOX	Patient diary	No correlation between FeNO and clinical characteristics.	−
Franklin et al^Citation113	155 children (mean age: 1 1.5 ± 2.3 yrs)	Prospective birth cohort	Sievers NOA 280i	Modified ATS questionnaire	FeNO was not associated with symptoms (recent wheeze), P = 0.53.	−
Jones et al^Citation114	78 mild/moderate asthma patients (age: 18–74 yrs)	Prospective, max 6 weeks or to LOC	Unknown	LOC based on: lung function decrease, increase bronchodilator use, nocturnal asthma symptoms, distressing asthma symptoms	Good correlation between FeNO at final study visit, change of FeNO over time and symptom score (r = 0.33, P = 0.004, r = 0.45, P < 0.0001, respectively). Single FeNO measurements and changes of FeNO had PPV that ranged from80% to 90% for predicting and diagnosing LOC.	+
Sippel et al^Citation115	100 asthma patients (age: 7–80 yrs)	Cross-sectional	Sievers NOA 280i	Questionnaire based on National Heart, Blood and Lung Institute Epidemiology Standardization project/dyspnea score	FeNO significantly correlated with asthma symptoms within the past 2 weeks (P = 0.02), dyspnea score (P = 0.02) and daily use of rescue medications (P = 0.01).	+

Abbreviations: ACQ, Asthma Control Questionnaire; ACT, Asthma Control Test; ATS, American Thoracic Society; AUC, area under the receiver operating characteristic curve; CAN, Control de Asma en Ninõs; FeNO, fraction of exhaled nitric oxide; GINA, Global Initiative for Asthma; ICS, inhaled corticosteroids; JTFPP, Joint Task Force Practice Parameter; LTRA, leukotriene receptor antagonist; NAEPP, National Asthma Education and Prevention Program; LOC, loss of asthma control; NPV, negative predictive value; PPV, positive predictive value; RCT, randomized controlled trial; wks, weeks; yrs, years; CI, confidence interval.

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