Abstract
Rationale: Nonadherence to inhaled corticosteroid therapy (ICS) is a major contributor to poor control in difficult asthma, yet it is challenging to ascertain.
Objectives: Identify a test for nonadherence using fractional exhaled nitric oxide (FeNO) suppression after directly observed inhaled corticosteroid (DOICS) treatment.
Methods: Difficult asthma patients with an elevated FeNO (>45 ppb) were recruited as adherent (ICS prescription filling >80%) or nonadherent (filling <50%). They received 7 days of DOICS (budesonide 1,600 μg) and a test for nonadherence based on changes in FeNO was developed. Using this test, clinic patients were prospectively classified as adherent or nonadherent and this was then validated against prescription filling records, prednisolone assay, and concordance interview.
Measurements and Main Results: After 7 days of DOICS nonadherent (n = 9) compared with adherent subjects (n = 13) had a greater reduction in FeNO to 47 ± 21% versus 79 ± 26% of baseline measurement (P = 0.003), which was also evident after 5 days (P = 0.02) and a FeNO test for nonadherence (area under the curve = 0.86; 95% confidence interval, 0.68–1.00) was defined. Prospective validation in 40 subjects found the test identified 13 as nonadherent; eight confirmed nonadherence during interview (three of whom had excellent prescription filling but did not take medication), five denied nonadherence, two had poor inhaler technique (unintentional nonadherence), and one also denied nonadherence to prednisolone despite nonadherent blood level. Twenty-seven participants were adherent on testing, which was confirmed in 21. Five admitted poor ICS adherence but of these, four were adherent with oral steroids and one with omalizumab.
Conclusions: FeNO suppression after DOICS provides an objective test to distinguish adherent from nonadherent patients with difficult asthma.
Clinical trial registered with www.clinicaltrials.gov (NCT 01219036).
Nonadherence to inhaled and oral corticosteroid treatment is a common contributing factor in difficult asthma (symptomatic despite Global Initiative for Asthma Step 4 and 5 treatment). Fractional exhaled nitric oxide (FeNO) is a surrogate measure of airway inflammation and may have a role in monitoring response to inhaled corticosteroids. An objective clinical test for nonadherence in difficult asthma has not been previously described.
This study demonstrates the use of FeNO suppression after directly observed inhaled corticosteroids to distinguish adherent refractory asthma from nonadherent mild to moderate persistent asthma in a difficult asthma population. The FeNO suppression test can identify patients nonadherent to inhaled corticosteroid therapy, and also patients who fill prescriptions for this treatment but do not take the medication. Identifying nonadherence is important, because it allows improved patient characterization and tailoring of asthma management to individual needs.
The term “difficult asthma” refers to patients who remain symptomatic despite treatment at Global Initiative for Asthma Guidelines Steps 4 and 5, accounting for 5–10% of adults with asthma (1). Nonadherence to inhaled corticosteroids (ICS) is a major contributing factor to treatment failure (2–4), with nonadherence rates based on prescription filling between 35% and 65% (5, 6). In these studies, nonadherence was associated with poor asthma outcomes, including recurrent hospital admission and previous ventilation (5, 6).
The assessment of nonadherence in this population is challenging (6) and currently no simple objective measure of adherence to ICS therapy exists. Studies in difficult asthma have used prescription refill records as a surrogate measure of adherence; however, this approach is not without limitations. Poor prescription filling may confirm nonadherence, yet satisfactory prescription filling does not mean that the medication is actually taken. Prescription refill records give information on adherence over a period of months but ignore short-term adherence behavior. Prescription data also depend on information systems that are not widely available and multiple prescription outlets frequently make accurate data impossible to obtain.
It has been suggested that fractional exhaled nitric oxide (FeNO) may play a role in identifying nonadherence (7, 8). FeNO is a well-tolerated, reproducible, noninvasive surrogate marker of airway inflammation in asthma (8, 9) and correlates with eosinophilic airways inflammation (10, 11). In mild asthma, FeNO levels decrease within days after corticosteroid treatment in a dose-dependent fashion, and increase after steroid withdrawal (12). Steroid-naive subjects with raised FeNO levels demonstrate a significantly greater response to ICS resulting in improved symptoms, FEV1, morning peak flows, and airway hyperresponsiveness (13). Elevated FeNO levels have been observed in difficult asthma despite high-dose corticosteroid treatment (14) implying either insufficient treatment or nonadherence, or much less commonly, a steroid-resistant inflammatory process. In difficult asthma, raised FeNO levels have been shown to predict attainable asthma control with high-dose ICS and oral steroids (15). Although FeNO has been disappointing in tailoring the response to asthma treatment (16), occasional studies have been positive (17) and correlations between adherence with ICS treatment in clinical trials and a reduction in FeNO have been reported (18, 19). The current study (1) examined the utility of FeNO at initial clinical assessment in identifying nonadherence and (2) sought to develop a practical objective procedure for assessing nonadherence in difficult asthma using FeNO suppression after directly observed inhaled steroid therapy (DOICS). Our hypothesis was that the magnitude of FeNO suppression after DOICS would distinguish poor adherence in difficult asthma from refractory asthma. Some of the results of these studies have been previously reported in the form of abstracts (20–22).
This two-stage study recruited patients attending the Northern Ireland Regional Difficult Asthma Service with persisting symptoms despite Global Initiative for Asthma Step 4 and 5 treatment (1). Stage 1 examined the role of baseline FeNO at initial assessment in identifying poor adherence. Stage 2 prospectively examined if DOICS with FeNO monitoring could identify nonadherence. Stage 2 was performed in two phases: proof of concept and validation. In all studies current smokers were excluded. The study was approved by the Regional Ethics Committee; registered on clinical trials.gov (study number NCT 01219036); and written informed consent was obtained.
We examined new referrals (January 2007 to December 2010) with ICS prescription records and corresponding FeNO measured at initial clinic attendance. Patient demographics, lung function, and prescribed medications were recorded.
Patients with a persistently elevated FeNO (>45 ppb on two sequential occasions) including new referrals and review patients were recruited for DOICS.
The reference standard for adherence was defined as prescription filling greater than 80% (previous 6 mo) with concordance interview confirming adherence. Nonadherence was defined as ICS prescription refilling less than 50%. We have previously described and validated our methodology for defining nonadherence in this population using prescription records and prednisolone levels and concordance interviewing with these data (6). To ensure the study did not alter participant’s adherence behavior, all subjects were informed that the study was designed to examine the effect of inhaled steroid on airways inflammation, without reference to adherence. Subjects received 7 consecutive days of DOICS (budesonide, 1,600 μg by Turbohaler, AstraZeneca UK Ltd, Bedfordshire, UK) with daily FeNO measurement for 8 days, then weekly for 4 weeks. After 7 days DOICS, patients with FeNO greater than 40 ppb received intramuscular triamcinolone, 80 mg, to demonstrate FeNO responsiveness to high-dose systemic corticosteroids. Sputum induction and asthma control questionnaire (ACQ) were performed on the first visit, after 7 days of DOICS, and at the end of the study. A test for nonadherence based on changes in FeNO at 5 and 7 days was developed.
Participants underwent the FeNO suppression test for nonadherence as detailed previously and were classified as adherent or nonadherent. Prescription filling records, prednisolone assay, concordance interview, and inhaler technique assessment were used to validate adherence status (see online supplement) (6).
FeNO was measured using a NIOX MINO (Aerocrine AB, Stockholm, Sweden) according to American Thoracic Society/European Respiratory Society recommendations at a 50 ml/s flow rate (23). Sputum induction and processing were performed using established methods (24, 25). Asthma control was assessed using the ACQ (26). Spirometry was measured according to American Thoracic Society/European Respiratory Society guidelines (27).
Prescription refill rates were calculated from general practitioner prescription records for a 6-month time period (see online supplement) (6). Plasma prednisolone and cortisol assay levels were performed on patients taking oral steroids, as previously described (2, 6).
Data were analyzed using SPSS for Mac, version 16 (SPSS, Chicago, IL). Between-group comparisons were made using independent t testing or Mann-Whitney U tests as appropriate. Nominal variables were examined using chi-square analysis. Nonparametric correlation analysis was performed. A P value of less than 0.05 was considered significant. In stage 2, FeNO measurements were log transformed. Logistic regression and receiver operator characteristic analyses were performed to identify the optimum performance characteristics of the test for nonadherence, based on the ratio of FeNO measurements before and after DOICS.
From January 2007 to December 2010, 213 new referrals were assessed and 146 were eligible for analysis. Reasons for exclusion were as follows: 38 patients, no FeNO documented; two unable to perform FeNO; 10 patients, no prescription records available; and 17 current smokers. Patient characteristics are shown in Table 1. There was no significant correlation between baseline FeNO and ICS prescription refill ratio (r = −0.11; P = 0.2). Usual “cut-points” to define poor adherence are less than 80% prescription filling and very poor adherence less than 50% filling. There was no difference in FeNO levels between these groups (<80%, median FeNO 55 ppb, interquartile range [IQR] 23–97 vs. 37 ppb, IQR 18–76; P = 0.1) and less than 50% (median FeNO 49 ppb, IQR 21–92 vs. 45 ppb, IQR 20–87; P = 0.7). Similarly, defining an elevated FeNO as greater than 45 ppb and very high FeNO as greater than 100 ppb, there was no difference in the prescription refill rate above and below each cut-point (>45 ppb ICS refill rate median 67%, IQR 36–100 vs. 100% IQR, 50–112; P = 0.19; >100 ppb median refill rate 69%, IQR 33–108 vs. 92%, IQR 50–106; P = 0.58).
| Patient Characteristic | N = 146 |
| Age, yr* | 40.6 ± 15.1 |
| Sex, F/M | 100/46 |
| Inhaled corticosteroid, BDP equivalent μg† | 1,600 (800–2,000) |
| Long-acting β-agonist, n (%) | 142 (97) |
| Theophylline, n (%) | 75 (51) |
| Maintenance oral steroids, n (%) | 47 (32) |
| FEV1, % predicted* | 79 ± 24 |
| FEV1/FVC ratio, %* | 69 ± 13 |
| FeNO, ppb† | 46 (21–89) |
| <50% ICS prescription refill, n (%) | 45 (31) |
| <80% ICS prescription refill, n (%) | 67 (46) |
Using baseline FeNO greater than 45 ppb as a potential marker for nonadherence and defining nonadherence as less than 80% ICS prescription refill ratio resulted in a negative predictive value (NPV) of 0.63 (95% confidence interval [CI], 0.51–0.73) and a positive predictive value (PPV) of 0.54 (95% CI, 43–0.65). At a less than 50% prescription refill ratio cut-off, the NPV was 0.71 (95% CI, 0.6–0.81) and PPV was 0.33 (95% CI, 0.23–0.44). Using FeNO greater than 100 ppb, NPV and PPV were 0.55 (95% CI, 0.46–0.64) and 0.52 (95% CI, 0.33–0.7) for less than 80% ICS prescription refill and 0.69 (95% CI, 0.61–0.77) and 0.32 (95% CI, 0.17–0.52) for less than 50% prescription refill.
Twenty-two subjects (9 nonadherent, 13 adherent based on prescription records) were enrolled into the proof of concept study. Demographic details, medication, and health care use for the study population are available in Table 2. There was a nonsignificant trend for nonadherent participants to have a higher baseline FeNO than adherent subjects (107 ppb [87–154] vs. 72 ppb [55–101]; P = 0.07). After 7 days of DOICS nonadherent subjects had a significantly greater reduction in their FeNO level to 47 ± 21% versus 79 ± 26% of baseline measurement (P = 0.003), which was also evident after 5 days of DOICS (54 ± 24% vs. 77 ± 24%; P = 0.02) (Figure 1) (see Figure E1 in the online supplement).
| Proof of Concept | ||||
| Nonadherent | Adherent | P Value | Validation | |
| N | 9 | 13 | — | 40 |
| Female, n (%) | 8 (89) | 4 (31) | 0.02 | 23 (58) |
| Age, yr | 43.1 ± 19.8 | 53.1 ± 13.3 | ns | 46.6 ± 14.5 |
| BMI, kg/m2 | 31.1 ± 6.9 | 27.8 ± 3.2 | ns | 29.4 ± 6.6 |
| FEV1, L | 2.24 ± 0.76 | 2.33 ± 0.75 | ns | 2.23 ± 0.62 |
| FEV1, % predicted | 83 ± 17 | 72 ± 21 | ns | 76 ± 25 |
| FVC, L | 3.06 ± 0.55 | 4.08 ± 0.98 | 0.01 | 3.60 ± 0.92 |
| FVC, % predicted | 89 ± 14 | 96 ± 15 | ns | 97 ± 18 |
| FEV1/FVC ratio, % | 72 ± 16 | 57 ± 13 | 0.03 | 63 ± 14 |
| Hospital admissions in the previous 12 mo, n* | 0 (0–1.5) | 0 (0–0) | 0.03 | 0 (0–1) |
| Exacerbations in the previous 12 mo, n* | 3 (2.5–5) | 2 (1–4.5) | ns | 4 (2–5) |
| ICU admission, n (%) | 2 (22) | 1 (8) | ns | 8 (20) |
| BDP equivalent dose, μg* | 1,600 (800–2,000) | 1,600 (800–2,000) | ns | 1,600 (950–2,000) |
| LABA, % | 100 | 100 | ns | 100 |
| Maintenance oral steroids, % | 66 | 77 | ns | 58 |
| Oral steroid dose, mg* | 10 (9–13) | 10 (5–10) | ns | 10 (9–15) |
| LRTA, % | 22 | 31 | ns | 43 |
| Theophylline, % | 56 | 85 | ns | 75 |
| Omalizumab, n | 0 | 1 | ns | 2 |
| Steroid-sparing agents, n | 0 | 2 | ns | 3 |
| IgE | 192 (90–330) | 203 (45–322) | ns | 161 (56–372)† |
| Blood eosinophil count | 0.34 (0.28–0.43) | 0.45 (0.22–0.88) | ns | 0.34 (0.19–0.61) |
| Atopy, n (%) | 7 (78) | 9 (69) | ns | 34 (85) |
| Intramuscular triamcinolone administered Day 7, n (%) | 5 (56) | 10 (77) | ns | — |
Figure 1. Proof of concept (phase 1). Nonadherent (n = 9; gray circles) and adherent patients (n = 13; black squares) were given directly observed inhaled steroid treatment (DOICS) for 7 days with daily fractional exhaled nitric oxide (FeNO) measurement. After 7 days of DOICS, nonadherent subjects had a significantly greater reduction in their FeNO level to 47 ± 21% versus 79 ± 26% of baseline measurement (P = 0.003), which was also evident after 5 days of DOICS (P = 0.02).
[More] [Minimize]Tests for nonadherence using 7- and 5-day DOICS were determined using logistic regression and receiver operating characteristic analysis (see online supplement): 7-day DOICS, area under the curve = 0.88 (95% CI, 0.72–1.00; SEM 0.08) (see Figure E2) and 5-day DOICS area under the curve = 0.86 (95% CI, 0.68–1.00; SEM 0.09) (Figure 2). The 5-day DOICS test was chosen because it is a more clinically pragmatic test, avoiding the weekend when delivered in an outpatient setting: after 5 days of DOICS, the FeNO result that optimally defined nonadherence was Lg10ΔFeNO greater than or equal to 0.24 (sensitivity = 0.78, 95% CI, 0.45–0.94; specificity = 0.92, 95% CI, 0.67–0.99).
Figure 2. Receiver-operator characteristic analysis to determine the clinical test to identify nonadherence. The area under the curve (AUC) was 0.86 (SEM 0.09) for a test using 5 days of directly inhaled steroid treatment. Nonadherence was identified as Lg10ΔFeNO greater than or equal to 0.24. Lg10ΔFeNO was defined as {mean (Lg10 FeNO Day 0, Lg10 FeNO Day 1)} - {mean (Lg10 FeNO Day 4, Lg10 FeNO Day 5)}. FeNO = fractional exhaled nitric oxide.
[More] [Minimize]Lg10ΔFeNO = {mean (Lg10 FeNO Day 0, Lg10 FeNO Day 1)} - {mean (Lg10 FeNO Day 4, Lg10 FeNO Day 5)}. In effect, a 42% fall in FeNO between the Day 0–Day 1 and the Day 4–Day 5 mean values equates with nonadherence with inhaled steroid.
Nonadherent subjects had higher baseline ACQ scores (3.17 ± 0.7 vs. 1.68 ± 0.99; P = 0.02). After 7 days of DOICS both groups improved, although this was only greater than the minimal clinically significant improvement for the nonadherent subjects (Day 0 vs. Day 7 ACQ, nonadherent 3.17 ± 0.70 vs. Day 7, 2.56 ± 0.78; P = 0.004; adherent [n = 13], 1.68 ± 0.99 vs. 1.30 ± 0.87; P = 0.018) (change in ACQ: nonadherent 0.62 ± 0.47 vs. adherent 0.37 ± 0.49; P = 0.26). There was no difference between sputum eosinophil counts at baseline (nonadherent [n = 8] median 5.5% [IQR, 2.1 – 9.8]; adherent [n = 8] 11.2% [2.4–43]; P = 0.35). Sputum eosinophil counts for both groups fell after DOICS; however, this was only significant for the adherent group (adherent [n = 6] Day 0, median 22%, IQR 3.3–53.7 vs. Day 7, 11.9%, IQR 3.7–21.3, P = 0.046; nonadherent [n = 4] Day 0, 5.2%, IQR 1.3–31.9 vs. Day 7, 1.2%, IQR 0.2–18.2; P = 0.68).
Intramuscular triamcinolone was administered to 5 nonadherent and 10 adherent subjects. All but three subjects had their FeNO levels suppressed to below 50 ppb (the three nonresponders had FeNO levels >100 ppb during the 4-wk follow-up and all were adherent subjects). The FeNO of nonadherent participants (n = 4) who did not receive triamcinolone decreased to 42 ± 18% of baseline FeNO after DOICS and over the next 4 weeks two patients’ FeNO remained suppressed (33% and 65% of baseline FeNO), one returned to baseline (101% of baseline FeNO) and one increased to 148% of baseline FeNO. Each of the three adherent subjects who were not administered triamcinolone returned to their baseline FeNO levels (95%, 103%, and 107% of baseline FeNO) after DOICS (Figure 3).
Figure 3. Responses to directly observed inhaled steroid treatment and intramuscular triamcinolone, administered on study Day 7. (A) Changes in fractional exhaled nitric oxide (FeNO) of nonadherent subjects who received triamcinolone (n = 5; black squares) and those who did not (n = 4; gray circles). (B) Changes in FeNO of adherent subjects who received triamcinolone (n = 10; black squares) and those who did not (n = 4; gray circles). FeNO was suppressed below 50 ppb in all but three subjects, who all had FeNO levels greater than 100 ppb during the 4-week follow-up and all were adherent subjects.
[More] [Minimize]Two hundred and twenty-nine patients were screened for inclusion and 40 were evaluated (115 did not have a persistently elevated FeNO, 4 were smokers, 1 was pregnant, 58 declined to participate, 9 recruited subjects had a FeNO level <45 ppb on study Day 0 post-recruitment, and 2 subjects self-modified their oral corticosteroid dose during the actual study). The 40 participants underwent 5 days of DOICS and 13 were test defined as nonadherent with Lg10ΔFeNO greater than or equal to 0.24. Twenty-seven participants were adherent. There was a trend for participants identified as adherent to have greater ICS prescription filling than nonadherent subjects (P = 0.066).
Of the 13 subjects identified as nonadherent by the test, 8 confirmed nonadherence to ICS during concordance interview; three of these had good ICS prescription filling (89%, 133%, 167%) but admitted during interview to not taking medication and two participants were incorrectly using their metered dose inhaler corticosteroid inhaler (unintentional nonadherence). Three subjects denied nonadherence during interview despite test results: one of these had an undetectable prednisolone level and normal cortisol level, indicating nonadherence to oral steroid therapy (which was also denied).
Of 27 participants identified as adherent, 21 were confirmed as adherent to ICS by prescription records and adherence interview. Five subjects admitted poor adherence with ICS, although four of these were confirmed to be adherent to maintenance oral steroids on prescription filling and blood testing (prednisolone and cortisol levels). The remaining subject was receiving subcutaneous omalizumab. Of interest, one participant who had 33% ICS prescription filling reduced their FeNO by 48% (46 ppb) in 5 days between recruitment and study participation, consistent with adherence to ICS during this period.
Comparison of the FeNO test with a composite adherence measure comprising prescription records, adherence interview, blood testing, and inhaler technique revealed sensitivity of 0.67 (95% CI, 0.44–0.84) and specificity of 0.95 (95% CI, 0.78–0.99) with NPV 0.78 (95% CI, 0.59– 0.89) and PPV 0.92 (95% CI, 0.67–0.99) to identify nonadherence.
This study demonstrates that suppression of FeNO after directly observed treatment with ICS differentiates patients with difficult asthma who are adherent to ICS treatment from those who are not. Furthermore, this objective FeNO test can identify nonadherent patients who fill prescriptions for this treatment but do not actually take the medication. The use of the FeNO test improves the challenging process of identifying nonadherence to ICS, resulting in improved patient characterization, and allows nonadherence to be addressed. Additionally, we believe this test is useful in stratifying patients who are being considered for complex and expensive biologic therapies, because if FeNO falls rapidly after DOICS, this identifies subjects who are presumed to have refractory disease but are in fact not receiving adequate inhaled steroid treatment.
We have shown that a single elevated FeNO at initial assessment at a difficult asthma service is not an accurate discriminator of ICS nonadherence in clinical practice. This is because some patients with severe asthma who are taking high-dose ICS treatment have a persistently elevated FeNO. Previous studies in pediatric asthma populations have highlighted a correlation between elevated FeNO levels and nonadherence, using differing methodologies (18, 19, 28). One study counted residual doses during sequential changes of ICS and demonstrated a positive correlation between adherence with budesonide and a reduction in FeNO (n = 54; P = 0.0003; r2 = 0.59) (18). In another study, patients who exhibited poor self-reported compliance (defined as taking <49% of their prescribed regime) had significantly higher FeNO than those with good compliance (>75% of prescribed regime; P = 0.001; n = 30) (19). In a pediatric population, self-reported ICS adherence was the only clinical factor that correlated significantly with FeNO (n = 67; P = 0.017) (28). However, not all studies have reported a relationship between FeNO and adherence. A trial using an electronic ICS medication monitoring device reported weak correlations between FeNO and both days prescribed dose was taken (n = 20; P = 0.67; r = 0.055) and dose compliance (P = 0.24; r = 0.055) (29). It is important to recognize that statistical correlations between adherence and FeNO levels cannot be extrapolated to clinical utility, particularly in a more difficult to manage population. This is because there is substantial individual variation and as we have demonstrated a high FeNO is frequently seen in patients with severe asthma despite adherence with high-dose ICS. However, examining the dynamic effect, specifically suppression of FeNO with DOICS, rather than a single cross-sectional measurement, can identify nonadherence in a difficult asthma population.
The FeNO suppression test is targeted toward difficult asthma patients with elevated FeNO levels (>45 ppb), which accounts for approximately half of the patients attending the Northern Ireland difficult asthma service. Above this FeNO level, steroid-naive subjects display a greater response to ICS (13). An audit of four specialist difficult asthma clinics in the United Kingdom, including Belfast, found similar FeNO levels between specialist centers, with an overall median FeNO 34.5 ppb (IQR, 16–65) in 133 patients (30). Data from the Severe Asthma Research Program suggest that high FeNO levels in this subset of patients recognizes an “at-risk” phenotype with significant airway reactivity, airflow limitation, decreased awareness of their symptoms, and greatest use of emergency care (31). These patients are more likely to be prescribed oral corticosteroids and have higher short-acting β agonist (SABA) dispensing rates (31, 32). These are all features that we have previously described in a nonadherent population (6) and nonadherence may therefore be regarded as a contributor to the at-risk phenotype. The need for objective assessment of nonadherence in patients with persistent symptoms and ongoing morbidity despite prescription of high-dose therapy is essential to target management appropriately.
Administering intramuscular triamcinolone to adults and children with difficult asthma results in a significant reduction in FeNO that continues for up to 4 weeks (33, 34). It is notable that many patients in these studies had refractory asthma and those with nonresponding FeNO levels were deemed to have steroid resistance. In the present study, a small number of patients with elevated FeNO levels were “resistant” to DOICS and intramuscular triamcinolone. Apart from steroid resistance, alternative explanations include ongoing allergen exposure; alternative sources or conditions contributing to FeNO; or genetic factors, such as NOS polymorphisms. Alternative conditions, such as allergic rhinitis, causing persistently raised FeNO levels are an unlikely cause because they too are steroid sensitive and should improve with systemic steroids. Elevated FeNO levels despite systemic steroids may reflect NO production from NO synthases NOS1 and NOS3, which are not sensitive to steroid (35); however, these enzymes produce small amounts of NO as part of a local regulatory role (36). The response of FeNO to ICS has been shown to be normally distributed in children with asthma with a subgroup of patients with nonresponding FeNO levels to ICS treatment accounting for approximately 25% of the study population (37). Increased FeNO despite high-dose ICS was significantly related to bronchial hyperresponsiveness and allergy; however, the study failed to measure adherence (37).
Our inclusion criteria were kept relatively broad to give us a study cohort representative of our patient population and allow the development of a functional test viable for real-life clinical practice. The FeNO test is time-consuming, and is not suitable for widespread use in primary care; however, it is effective in this subset of patients attending a specialist difficult asthma clinic. This population generates significant healthcare spending and using resources to deliver this test is likely to be cost effective, particularly if adherence can be addressed and prevents progression to complex biologic therapies. In addition, implementation can be more efficiently delivered by adapting telemedicine systems (which we are currently exploring); availing of community nursing services; or attendance at a local healthcare center for DOICS and FeNO measurement. This test may also have a role in targeting biologic therapies appropriately and in mechanistic research studies, allowing nonadherence to be identified in patients before labeling as refractory asthma.
In keeping with a difficult asthma cohort, a large proportion of our study population was prescribed systemic steroids, including two thirds of nonadherent patients. In this subgroup, physicians often step-up treatment unaware of nonadherence to inhaled therapy, again highlighting the need for a clinically applicable test to identify this contributing factor. Adherence is not an “all or nothing” concept and patients can display a variety of patterns of medication use, with adherence varying in relation to different medications (38). Our data show some individuals adhering better to oral corticosteroid than to inhaled therapy, emphasizing the complexity of assessing adherence in difficult asthma. Such patients fail to suppress their FeNO after DOICS, despite poor inhaled steroid exposure, because they are receiving adequate antiinflammatory steroid therapy in oral form. However, these patients do have severe disease and the test still has utility in discriminating patients who are likely to have a significant response to inhaled steroid therapy alone. It is also important to acknowledge that adherence to each individual treatment is a continuous variable and to identify very poor adherence to ICS as a major contributing factor to poor asthma control we opted to dichotomize adherence. Analysis of various prescription refill cut-points to classify nonadherence suggests 80% consistently gives a fair balance between sensitivity and specificity compared with other adherence measures (self-report and electronic monitors) (39). In the proof of concept study we used a narrower definition of nonadherence, thereby improving the sensitivity of this definition.
Using prescription records alone as a reference standard for adherence is not without its limitations. Not collecting prescriptions can confirm nonadherence; however, because patients may stockpile medication the collection of prescriptions does not necessarily imply adherence. The FeNO test has the distinct advantage of being able to identify patients who on prescription filling seem adherent but in a concordance discussion based on the FeNO test admit to collecting their prescription but not taking their medication. Consequently, such individuals can have their management modified to address the reasons for their nonadherence to improve adherence and ultimately asthma control.
In the proof of concept phase there was higher prevalence of females in the nonadherent group. This may be explained by a potential relationship between adherence and sex. Several studies have previously reported this sex difference (40–43), including a difficult asthma study (6), but this is not a universal finding (44–46), nor has a reason been identified. This phase was unmasked and it was hoped that a reduction in FeNO with DOICS would give participants positive feedback regarding the effect of ICS treatment and improve adherence in nonadherent patients. About half of nonadherent individuals who suppressed with DOICS and did not receive systemic steroids continued to have a low FeNO over the 4 weeks of follow-up, suggesting the test may potentially have a behavioral effect, but this requires specific study.
Recruiting subjects with poor adherence to a clinical study can be problematic because they are often less likely to participate. To maximize recruitment and ensure participation did not modify medication-taking behavior, participants were not informed that adherence was being assessed in the study. Despite this, nine subjects had FeNO reductions to less than 45 ppb in the 5 days between recruitment and commencing the study, making them no longer eligible to participate. One participant who had a significant reduction in FeNO prestudy was found to have prescription filling of only 33%, suggesting that recruitment altered adherence behavior before DOICS.
In conclusion, the results of this study support the utility of FeNO suppression after DOICS to identify nonadherence to ICS in adults with difficult asthma. This clinical test seems to accurately identify nonadherence to ICS in this population, even when prescription-filling records are good. Identifying nonadherence allows appropriate tailored asthma management, and we plan to further validate this test in a multicenter difficult asthma population.
| 1. | Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention. 2011. Available from: http://www.ginasthma.org/. |
| 2. | Robinson DS, Campbell DA, Durham SR, Pfeffer J, Barnes PJ, Chung KF. Systematic assessment of difficult-to-treat asthma. Eur Respir J 2003;22:478–483. |
| 3. | Araujo AC, Ferraz E, Borges Mde C, Filho JT, Vianna EO. Investigation of factors associated with difficult-to-control asthma. J Bras Pneumol 2007;33:495–501. |
| 4. | Heaney LG, Conway E, Kelly C, Johnston BT, English C, Stevenson M, Gamble J. Predictors of therapy resistant asthma: outcome of a systematic evaluation protocol. Thorax 2003;58:561–566. |
| 5. | Murphy AC, Proeschel A, Brightling CE, Wardlaw AJ, Pavord ID, Bradding P, Green RH. The relationship between clinical outcomes and medication adherence in difficult-to-control asthma. Thorax 2012;67:751–753. |
| 6. | Gamble J, Stevenson M, McClean E, Heaney LG. The prevalence of nonadherence in difficult asthma. Am J Respir Crit Care Med 2009;180:817–822. |
| 7. | Dweik RA, Boggs PB, Erzurum SC, Irvin CG, Leigh MW, Lundberg JO, Olin AC, Plummer AL, Taylor DR. An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FeNO) for clinical applications. Am J Respir Crit Care Med 2011;184:602–615. |
| 8. | Taylor DR, Pijnenburg MW, Smith AD, De Jongste JC. Exhaled nitric oxide measurements: clinical application and interpretation. Thorax 2006;61:817–827. |
| 9. | Gustafsson LE, Leone AM, Persson MG, Wiklund NP, Moncada S. Endogenous nitric oxide is present in the exhaled air of rabbits, guinea pigs and humans. Biochem Biophys Res Commun 1991;181:852–857. |
| 10. | Jatakanon A, Lim S, Kharitonov SA, Chung KF, Barnes PJ. Correlation between exhaled nitric oxide, sputum eosinophils, and methacholine responsiveness in patients with mild asthma. Thorax 1998;53:91–95. |
| 11. | Payne DN, Adcock IM, Wilson NM, Oates T, Scallan M, Bush A. Relationship between exhaled nitric oxide and mucosal eosinophilic inflammation in children with difficult asthma, after treatment with oral prednisolone. Am J Respir Crit Care Med 2001;164:1376–1381. |
| 12. | Kharitonov SA, Donnelly LE, Montuschi P, Corradi M, Collins JV, Barnes PJ. Dose-dependent onset and cessation of action of inhaled budesonide on exhaled nitric oxide and symptoms in mild asthma. Thorax 2002;57:889–896. |
| 13. | Smith AD, Cowan JO, Brassett KP, Filsell S, McLachlan C, Monti-Sheehan G, Peter Herbison G, Robin Taylor D. Exhaled nitric oxide: a predictor of steroid response. Am J Respir Crit Care Med 2005;172:453–459. |
| 14. | Silkoff PE, Lent AM, Busacker AA, Katial RK, Balzar S, Strand M, Wenzel SE. Exhaled nitric oxide identifies the persistent eosinophilic phenotype in severe refractory asthma. J Allergy Clin Immunol 2005;116:1249–1255. |
| 15. | Perez-de-Llano LA, Carballada F, Castro Anon O, Pizarro M, Golpe R, Baloira A, Vazquez Caruncho M, Boquete M. Exhaled nitric oxide predicts control in patients with difficult-to-treat asthma. Eur Respir J 2010;35:1221–1227. |
| 16. | Petsky HL, Cates CJ, Lasserson TJ, Li AM, Turner C, Kynaston JA, Chang AB. A systematic review and meta-analysis: tailoring asthma treatment on eosinophilic markers (exhaled nitric oxide or sputum eosinophils). Thorax 2012;67:199–208. |
| 17. | Powell H, Murphy VE, Taylor DR, Hensley MJ, McCaffery K, Giles W, Clifton VL, Gibson PG. Management of asthma in pregnancy guided by measurement of fraction of exhaled nitric oxide: a double-blind, randomised controlled trial. Lancet 2011;378:983–990. |
| 18. | Beck-Ripp J, Griese M, Arenz S, Koring C, Pasqualoni B, Bufler P. Changes of exhaled nitric oxide during steroid treatment of childhood asthma. Eur Respir J 2002;19:1015–1019. |
| 19. | Delgado-Corcoran C, Kissoon N, Murphy SP, Duckworth LJ. Exhaled nitric oxide reflects asthma severity and asthma control. Pediatr Crit Care Med 2004;5:48–52. |
| 20. | McNicholl DM, Stevenson M, McGarvey LP, Heaney LG. The use of fractional exhaled nitric oxide in the identification of non-adherence in difficult asthma. Presented at the American Thoracic Society 2010 International Conference. May 14–19, 2010, New Orleans, LA. A3811. |
| 21. | McNicholl DM, Stevenson M, McGarvey LP, Heaney LG. Developing and validating a FeNO suppression test identifying non-adherence in difficult asthma. Presented at the American Thoracic Society International Conference 2011. May 13–18, 2011, Denver, CO. A4379. |
| 22. | McNicholl DM, McGarvey LP, Heaney LG. Is a high FeNO a marker of non-adherence in difficult asthma? Presented at the British Thoracic Society Winter Meeting 2011. Dec 7–9, 2011, London, UK. A8. |
| 23. | American Thoracic Society, European Respiratory Society. ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005. Am J Respir Crit Care Med 2005;171:912–930. |
| 24. | Paggiaro PL, Chanez P, Holz O, Ind P, Djukanovic R, Maestrelli P, Sterk P. Sputum induction. Eur Respir J 2002;20:3s–8s. |
| 25. | Efthimiadis A, Spanevello A, Hamid Q, Kelly MM, Linden M, Louis R, Pizzichini MM, Pizzichini E, Ronchi C, Van Overvel F, et al.. Methods of sputum processing for cell counts, immunocytochemistry and in situ hybridisation. Eur Respir J Suppl 2002;37:19s–23s. |
| 26. | Juniper EF, O'Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of a questionnaire to measure asthma control. Eur Respir J 1999;14:902–907. |
| 27. | Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright P, van der Grinten CP, Gustafsson P, et al.. Standardisation of spirometry. Eur Respir J 2005;26:319–338. |
| 28. | Cano-Garcinuno A, Carvajal-Uruena I, Diaz-Vazquez CA, Dominguez-Aurrecoechea B, Garcia-Merino A, de Rodas PM, Mora-Gandarillas I. Clinical correlates and determinants of airway inflammation in pediatric asthma. J Investig Allergol Clin Immunol 2010;20:303–310. |
| 29. | Katsara M, Donnelly D, Iqbal S, Elliott T, Everard ML. Relationship between exhaled nitric oxide levels and compliance with inhaled corticosteroids in asthmatic children. Respir Med 2006;100:1512–1517. |
| 30. | Heaney LG, Brightling CE, Menzies-Gow A, Stevenson M, Niven RM. Refractory asthma in the UK: cross-sectional findings from a UK multicentre registry. Thorax 2010;65:787–794. |
| 31. | Dweik RA, Sorkness RL, Wenzel S, Hammel J, Curran-Everett D, Comhair SA, Bleecker E, Busse W, Calhoun WJ, Castro M, et al.. Use of exhaled nitric oxide measurement to identify a reactive, at-risk phenotype among patients with asthma. Am J Respir Crit Care Med 2010;181:1033–1041. |
| 32. | Zeiger RS, Schatz M, Zhang F, Crawford WW, Kaplan MS, Roth RM, Chen W. Association of exhaled nitric oxide to asthma burden in asthmatics on inhaled corticosteroids. J Asthma 2011;48:8–17. |
| 33. | Panickar JR, Bhatnagar N, Grigg J. Exhaled nitric oxide after a single dose of intramuscular triamcinolone in children with difficult to control asthma. Pediatr Pulmonol 2007;42:573–578. |
| 34. | ten Brinke A, Zwinderman AH, Sterk PJ, Rabe KF, Bel EH. “Refractory” eosinophilic airway inflammation in severe asthma: effect of parenteral corticosteroids. Am J Respir Crit Care Med 2004;170:601–605. |
| 35. | Radomski MW, Palmer RM, Moncada S. Glucocorticoids inhibit the expression of an inducible, but not the constitutive, nitric oxide synthase in vascular endothelial cells. Proc Natl Acad Sci USA 1990;87:10043–10047. |
| 36. | Barnes PJ, Dweik RA, Gelb AF, Gibson PG, George SC, Grasemann H, Pavord ID, Ratjen F, Silkoff PE, Taylor DR, et al.. Exhaled nitric oxide in pulmonary diseases: a comprehensive review. Chest 2010;138:682–692. |
| 37. | Buchvald F, Eiberg H, Bisgaard H. Heterogeneity of FeNO response to inhaled steroid in asthmatic children. Clin Exp Allergy 2003;33:1735–1740. |
| 38. | Kelloway JS, Wyatt RA, Adlis SA. Comparison of patients' compliance with prescribed oral and inhaled asthma medications. Arch Intern Med 1994;154:1349–1352. |
| 39. | Hansen RA, Kim MM, Song L, Tu W, Wu J, Murray MD. Comparison of methods to assess medication adherence and classify nonadherence. Ann Pharmacother 2009;43:413–422. |
| 40. | Smith A, Krishnan JA, Bilderback A, Riekert KA, Rand CS, Bartlett SJ. Depressive symptoms and adherence to asthma therapy after hospital discharge. Chest 2006;130:1034–1038. |
| 41. | Williams LK, Joseph CL, Peterson EL, Moon C, Xi H, Krajenta R, Johnson R, Wells K, Booza JC, Tunceli K, et al.. Race-ethnicity, crime, and other factors associated with adherence to inhaled corticosteroids. J Allergy Clin Immunol 2007;119:168–175. |
| 42. | Williams LK, Joseph CL, Peterson EL, Wells K, Wang M, Chowdhry VK, Walsh M, Campbell J, Rand CS, Apter AJ, et al.. Patients with asthma who do not fill their inhaled corticosteroids: a study of primary nonadherence. J Allergy Clin Immunol 2007;120:1153–1159. |
| 43. | Chatkin JM, Cavalet-Blanco D, Scaglia NC, Tonietto RG, Wagner MB, Fritscher CC. Compliance with maintenance treatment of asthma (ADERE study). J Bras Pneumol 2006;32:277–283. |
| 44. | Naleway AL, Vollmer WM, Frazier EA, O'Connor E, Magid DJ. Gender differences in asthma management and quality of life. J Asthma 2006;43:549–552. |
| 45. | Krigsman K, Moen J, Nilsson JL, Ring L. Refill adherence by the elderly for asthma/chronic obstructive pulmonary disease drugs dispensed over a 10-year period. J Clin Pharm Ther 2007;32:603–611. |
| 46. | Corsico AG, Cazzoletti L, de Marco R, Janson C, Jarvis D, Zoia MC, Bugiani M, Accordini S, Villani S, Marinoni A, et al.. Factors affecting adherence to asthma treatment in an international cohort of young and middle-aged adults. Respir Med 2007;101:1363–1367. |
Supported by grants from Asthma UK and Northern Ireland Chest Heart and Stroke Association.
Author Contributions: All authors participated in conception and design; data collection, analysis, and interpretation; drafting and revising manuscript; and approval of final manuscript.
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org
Originally Published in Press as DOI:10.1164/rccm.201204-0587OC on September 28, 2012
Author disclosures are available with the text of this article at www.atsjournals.org.
