Role of fractional exhaled nitric oxide in pediatric asthma: An update

Asthma is the most common chronic respiratory disease in children. It is a heterogeneous disease and includes many phenotypes. Based on pathogenesis, asthma has been classified into Th2-high and non-Th2, known as asthma endotypes. Nitric oxide (NO) is an endogenous regulatory molecule involved in the pathophysiology of lung disease, including asthma. It acts as a bronchodilator, vasodilator, neurotransmitter, and mediator of inflammation. It is present in exhaled breaths. Fractional exhaled nitric oxide (FeNO) is a simple and noninvasive tool used to measure exhaled NO.[1] It is considered a biomarker of Th2 airway inflammation and correlates well with blood and sputum eosinophilia. In addition, it also correlates with serum immunoglobulin E level and skin prick test in atopic individuals.[2] It is given due consideration in diagnosing, monitoring, and selecting biological in asthma. Here, we summarized the recent update on the role of FeNO in pediatric asthma. FeNO can be measured by either chemiluminescence (CLD 88, Eco Medics, Switzerland) or electrochemical (NIOX VERO, Circassia, Sweden) analyzer. The former is highly accurate, but the equipment is expensive and requires regular calibration, whereas latter is simple, portable, and more cost-effective. Its unit of measurement is part per billion (ppb). Its value can be affected by several factors: age, sex, ethnicity, smoking, caffeine intake, etc. Standardization of equipment and method should be addressed before interpreting the result.[1] FeNO may predict future asthma development in school children.[2] In a study of 2568 asthma-free school children (7–10 years), there were two times increased risk of asthma development over 3 years of follow-up in children with higher FeNO than lower value (HR (Hazard ratio) 2.1; 95% CI 1.3–3.5).[3] The higher FeNO values were also associated with lower forced expiratory volume in 1 s and forced vital capacity.[2] The diagnosis of asthma requires the presence of characteristics, symptom patterns, and documentation of expiratory airflow limitation on spirometry. However, in children, asthma symptoms may be misleading, and spirometry may be normal or unable to perform adequately. The role of FeNO in asthma diagnosis is debatable. An adult study has shown that, at a cutoff value of 26 ppb, FeNO has higher diagnostic accuracy than the methacholine challenge test in diagnosing eosinophilic asthma. However, its value may be normal in some asthma phenotypes and during the exacerbation. Moreover, the cutoff value of FeNO for asthma diagnosis is not uniform; the American Thoracic Society (ATS) suggested >25 ppb, while the Global Initiative for Asthma (GINA) has taken >50 ppb as cutoff point.[1,4] Furthermore, FeNO is not specific for asthma, as its value may be increased in other allergic diseases, namely allergic rhinitis, atopic dermatitis, etc., and viral infection. As per GINA, FeNO does not help in ruling in or ruling out the diagnosis of asthma. Therefore, currently, FeNO has no role in the diagnosis of childhood asthma.[4] Studies have suggested role of FeNO in initiating inhaled corticosteroid (ICS), as patients with elevated FeNO levels have an excellent response to ICS therapy. Recent GINA guidelines suggest that in patients with suspected or confirmed asthma diagnoses, FeNO may help in decide to start ICS therapy but does not help to decide against treatment with ICS.[4] Based on the FeNO value, the ATS guideline classified pediatric asthma into three groups: <20 (low), 20–35 (indeterminate), and >35 ppb (high). Children with low FeNO values are unlikely to respond to ICS, while those with high values are likely to respond with ICS therapy. However, these cutoff values are not uniform and overlap with the healthy population.[1] ATS has given only conditional recommendations for FeNO testing with an initial diagnosis of asthma in addition to usual care in whom treatment is being considered.[5] The most promising role of FeNO is monitoring asthma control and tailoring ICS therapy. Many studies have suggested that FeNO-guided therapy results in better asthma control, less exacerbation, and the need for systemic steroid. Children having high FeNO levels are uncontrolled asthma and need to optimize ICS therapy. Those with low FeNO levels have controlled asthma and are less likely to develop exacerbation, thus therapy can be stepped down. Children with indeterminate values need close monitoring. In a Cochrane meta-analysis in children with asthma, FeNO-guided therapy was associated with a significant reduction in asthma exacerbation (odds ratio 0.67; 95% CI 0.51–0.90) compared to symptoms-guided therapy but did not improve daily symptoms and ICS doses.[6] In another meta-analysis, FeNO-guided therapy reduced asthma exacerbation and improved lung function in children but at the cost of increased daily ICS doses.[7] However, in a recent multicenter clinical trial in children (RACCENO), FeNO-guided treatment did not reduce asthma exacerbation over 12 months.[8] Therefore, FeNO-guided therapy cannot be recommended in children.[4] FeNO has a vital role in managing poorly controlled asthma. It helps to identify adherence to ICS. Elevated FeNO indicates poor adherence to therapy and a risk of frequent and severe exacerbation. FeNO also helps to determine the response to oral corticosteroids and the selection of biologicals (omalizumab, dupilumab, and tezepelumab).[5,9,10] In conclusion, FeNO appears promising in diagnosing, initiating, monitoring, tailoring ICS therapy, and selecting biological agents in asthma management. The major limitation of the widespread use of FeNO in clinical practice is the lack of robust evidence, ethnicity-specific normative cutoff value, and costly equipment. There is an urgent need for more research in this area from India.