Background

Asthma is a chronic inflammatory disorder of the airways, characterized by varying degrees of airflow obstruction. Bronchoconstriction, inflammatory cell infiltration, and airway edema reduce airflow intermittently, often in response to specific exposures, resulting in respiratory symptoms.¹ In the United States (U.S.), the current prevalence of asthma has increased over the past decade, from an estimated 22.2 million Americans in 2005 to 24.0 million Americans in 2014.^{2, 3} Asthma can significantly affect patients’ and families’ quality-of-life and ability to pursue activities such as school, work, and exercise. Globally, asthma ranks 14^th based on the burden of disease, as measured by disability adjusted life years.⁴ In US, asthma contributes significantly to health care resource utilization and associated costs. For example, in 2012, asthma was one of the top 20 leading diagnosis groups for primary care visits and was the main reason for 1.8 million emergency department visits and 439,000 hospitalizations. Although the severity of disease varies among patients and over time in the same patient, asthma can be fatal, accounting for approximately one death per 100,000 Americans.⁵

Diagnosing asthma is challenging. The common symptoms, such as shortness of breath, wheezing, and cough, are relatively non-specific. Various tests, including spirometry pre and post bronchodilator, and bronchoprovocation challenge, may be used by clinicians to aide in the diagnosis of asthma in the appropriate clinical context. However, the diagnosis remains clinical, based on compatible symptoms and evidence of reversible airway obstruction; no single criterion standard diagnostic test exists. More recently, fractional exhaled nitric oxide (FeNO) concentration has been added to the list of tests that clinicians may use to diagnose asthma, select treatment options, and monitor the response to therapy.

Nitric oxide (NO) is a gas normally found in each exhaled breath in all humans. Patients with asthma often have increased levels of inducible nitric oxide synthase (iNOS2), the enzyme that produces NO in their airway epithelium. Patterns of airway inflammation in asthma are heterogenous. Atopic asthma appears to be associated with a Th2 cytokine pattern of inflammation, with increased levels of IL4,IL5, and IL13. Th2 inflammation is also associated with elevated IgE levels and eosinophilia. IL13 production leads to an influx of eosinophils to inflamed tissue and their continued presence there. IL5 leads to eosinophil differentiation, maturation and activation. Sampling airway tissue, or even evaluating sputum for eosinophilia, can be technically difficult, and labor intensive. FeNO measurement has been evaluated as a surrogate biomarker for eosinophilia/Th2 inflammation. Studies evaluating specific therapies targeting the cytokines involved in Th2 inflammation individually suggest that blocking IL13 leads to a reduction in FeNO levels, whereas reductions in IL-5 do not cause reduction in FeNO levels.⁶

FeNO can be measured by exhalation into an analyzer. It has been found to be elevated in patients with atopic asthma (i.e., asthma associated with either positive skin test or specific IgE to aeroallergens) and was shown to correlate modestly with eosinophilia in sputum and endobronchial biopsy in steroid-naïve patients.^7–11 It has also been found to be elevated in both children and adults with atopy without a diagnosis of asthma, (eg atopic rhinitis).^{12, 13}

FeNO levels in atopic patients appear to correlate with number of positive skin prick tests and tests of bronchial hyperresponsiveness.¹³ There is a significant overlap in patients with atopic upper and lower respiratory tract disease, and other studies have found occult obstruction on pulmonary function testing in patients with chronic rhinosinusitis.¹⁴

In young children, the diagnosis of asthma is particularly challenging, given their inability to perform some of the diagnostic tests used in older individuals and the high prevalence of wheezing in children with respiratory infections. One potential use of FeNO is to predict which children who have repeated episodes of wheezing are likely to be diagnosed with asthma later in childhood. There are some data to suggest that FeNO compares favorably to other predictive tests to address the challenges in such children.^15–17

In individuals who have been diagnosed with asthma, FeNO may be useful to predict which treatments are likely to be most helpful to a given patient, to follow the response to treatment, or to aid in the assessment of adherence to certain therapies (e.g., inhaled corticosteroids).¹⁸ Ascertaining whether a patient has ‘responded” to a given therapy can be difficult, given the inherent variability in the disease, the non-specific nature of many measures of response, and the time required to demonstrate an effect of treatment. In addition, as an inflammatory marker, FeNO may also identify patients in whom non-compliance with anti-inflammatory medications (such as inhaled corticosteroids) may be an issue.

Multiple factors may confound the interpretation of FeNO data. These include asthma phenotype, atopy, use of inhaled or oral corticosteroids, patient’s weight, and age. In addition, FeNO measurements can be affected by acute changes proximal to the time of testing, such as exposure to tobacco smoke, use of bronchodilators, fasting state or food intake, or use of mouthwash. Moreover, the criteria for the “normal” range of FeNO (and the level considered diagnostic of a disease state, such as asthma) and the level of change in FeNO that is clinically significant remain uncertain.

Purpose and Scope of the Systematic Review

In 1989, the National Heart, Lung and Blood Institute (NHLBI) of the National Institutes of Health initiated the National Asthma Education and Prevention Program (NAEPP) to address growing concern about asthma in the US. One of the first accomplishments of the NAEPP was to convene a panel of experts who produced a report, National Asthma Education and Prevention Program Expert Panel Report (EPR): Guidelines for the Diagnosis and Management of Asthma, in 1991. The guidelines address the diagnosis, evaluation, and treatment of asthma. Given the most recent report, EPR-3, was published in 2007,¹ NHLBI assessed the need for an update by requesting information from the public, NAEPP Coordinating Committee Members and its affiliates, and members of the 2007 Expert Panel. Collected information was provided to the NHLBI Advisory Council Asthma Expert Working Group, which produced a report to summarize the process and recommendations from their needs assessment.¹⁹ The Working Group identified six high priority topics that should be updated. For each topic, key questions meriting a systematic literature review were formulated. NHLBI engaged AHRQ to perform the systematic reviews through its Evidence-based Practice Centers (EPC). This document represents the systematic review of “The Role of FeNO in the diagnosis and treatment of asthma”. The review also will highlight areas of controversy and identify needs for future research on this priority area.

We address the following Key Questions (KQs) as they pertain to the PICOTS (population, interventions, comparisons, outcomes, timing, and setting) (Table 1). Figure 1 shows the analytic framework that we developed for this systematic review.

Table 1

PICOTS (population, interventions, comparisons, outcomes, timing, and setting).

Figure 1

Analytic framework.

Key Questions (KQs)

KQ 1.

What is the clinical utility of FeNO measurements in the management of asthma in addition to, or instead of, other tests that might be performed? Specifically,

• a: What is the diagnostic accuracy of FeNO measurement(s) for making the diagnosis of asthma in individuals ages 5 and older?
• b: What is the clinical utility of FeNO measurements in monitoring disease activity and asthma outcomes in individuals with asthma ages 5 and older?
• c: What is the clinical utility of FeNO measurements to select medication options (including steroids) for individuals ages 5 and older?
• d: What is the clinical utility of FeNO measurements to monitor response to treatment in individuals ages 5 and older?
• e: In children ages 0–4 years with recurrent wheezing, how accurate is FeNO testing in predicting the future development of asthma at age 5 and above?