FeNO: Effective diagnostic for asthma? Influence of allergic rhinitis and atopy on its values
– a meta-analysis
Caeiro, Alexandra, “mimed08003@med.up.pt”; Coelho, Ana Margarida “mimed08025@med.up.pt”;
Abreu, Ana Teresa “mimed08286@med.up.pt”; Guedes, Bruna Daniela “mimed08040@med.up.pt”;
Linhares, Daniela “mimed08070@hotmail.com”; Pita, Inês “”mimed08093@med.up.pt; Fonseca,
João Alberto “mimed08116@med.up.pt”; Gomez, Maria de La Salete “mimed08165@med.up.pt”;
Oliveira, Marta Isabel “mimed08173@med.up.pt”; Abreu, Vítor Alexandre “mimed08137@med.up.pt”;
Vasconcelos, Gisela “mimed08087@med.up.pt”.
Under the guidance of João Fonseca, MD, PhD, and Luís Silva, MD; Turma 3
ABSTRACT
Background Many studies have been developed to investigate the relation between FeNO values
and asthma; nonetheless, the reliability of this diagnostic test and its possible setbacks are not yet
fully understood due to the many influencing factors.
Aim To measure the effect of atopy and allergic rhinitis on FeNO.
Methods A systematic review was made based on a search for full text, peer-reviewed articles with
original data. The selection of the articles was made in 2 steps. Only articles using online FeNO
measurements were included; articles which participants had asthma or other confounding conditions
were excluded. In each phase an independent assessment of two reviewers was made, using a
Google Docs form for simplicity and efficacy.
Meta-analysis were performed with 6 articles grouped by condition, and subgroups of based in age
groups where measures were performed.
Results We obtained 616 articles, 17 of which were included in the qualitative analysis and 6 in the
meta-analysis. In the qualitative analysis, all articles showed a tendency for FeNO values to increase
in the presence of atopy or allergic rhinitis. All meta-analysis showed a significant (p<0.05) elevation
of FeNO. In individuals with atopy the mean raise was 10.00 ppb (95%CI: 8.55-11.45), in children
with allergic rhinitis it was 17.45 ppb (95% CI: 14.14-20.76, in adults with allergic rhinitis it was 12.25
ppb (95% CI: 8.07-16.43).
Conclusions The presence of either atopy or allergic rhinitis causes elevation of FeNO values.
Key-words: asthma, exhaled nitric oxide, rhinitis, atopy, allergy.
INTRODUCTION
Asthma is a common illness, defined as a chronic inflammatory disorder of the airways, and can be
classified into two types: allergic and non-allergic asthma [1]. Allergic asthma is an atopic condition –
atopy being an allergic hypersensitivity affecting parts of the body not in direct contact with the
allergen. Non-allergic asthma is triggered by factors other than allergens, such as emotional stress
and physical exertion.
During airway cells inflammation, enzymes of the nitric oxide (NO) synthase family in endothelial
airway cells produce more NO than usually
[2].
NO has a diverse range of effects, including non-
adrenergic, non-cholinergic neurotransmission and vascular and non-vascular smooth muscle
relaxation
[3].
In pathological situations NO is a pro-inflammatory mediator with immunomodulatory
effects.
Fractional Exhaled Nitric Oxide has been used since the beginning of the century as a biomarker of
airway inflammation. Nowadays, measurement of exhaled nitric oxide is widely used in respiratory
research and clinical practice [4], especially in monitoring and diagnosing asthma patients. However,
FeNO is affected by several interfering factors, including method of collection, time of the day,
expiratory flow rate, smoking habits, exercise, gender, height, age and respiratory tract infection [5,6,7].
With recent needs for the establishment of FeNO reference values, it is crucial to explore and
synthesize the information available about these confounding factors in asthma diagnosis based in
exhaled NO measurements.
Atopy[8] and allergic rhinitis[9] are both suspected of raise FeNO values in a significant way[8,9,10]. They
are both very common co-morbidities of asthma.
This systematic review seeks to determine the influence of atopy and allergic rhinitis on FeNO
values, in order to provide a better interpretation of this diagnostic test, and enable the establishment
of standardized FeNO values in clinical practice.
METHODS
This systematic review was based in several essential steps: query selection (process described in
appendix 1) and literature search, article selection, data extraction, statistical analysis and discussion
of the results (figure 1). The systematic literature search was performed on three different databases:
PubMed
[13],
ISI Web of Knowledge
[14]
and Scopus
[15]
and only peer-reviewed full-text articles with
original data, published after January 1rst 2001 and written in English, Portuguese or Spanish were
included. The resulting references were extracted and transferred to an Excel® database, where a
formula was created to organize them and prevent mistakes. For each selection and data extraction
step, articles were randomly attributed to two reviewers, preventing data crossing.
The article selection was divided in two phases: analysis of titles and abstracts and full texts analysis.
In the first step, 4 exclusion criteria were applied; in the second step 4 exclusion criteria were added
(figure 1, appendix 2). Divergences were discussed by the reviewers and a third reviewer was
required in the case of persistence.
For the data extraction, Google Docs forms were used (figure 1, appendix 2). Differences in data
extracted by different reviewers were discussed. The data was organized using SPSS.
Statistical Analysis
A descriptive (qualitative) and a quantitative (meta-analysis) were performed ([11],[12]). In the
qualitative analysis, FeNO variations in each article between diseased and healthy groups were
analysed as well as the article’s conclusion about the condition’s influence on FeNO. The final
conclusions were based in their global results. Participants’ age groups, atopy and allergic rhinitis
assessments were analysed too.
Articles selection for meta-analysis was primarily based on their summary and dispersion measures:
only those with mean and standard deviation (or measures that lead to it) could be used. Articles
were divided in two groups (atopy and allergic rhinitis) and subgroups were made based in
participants’ age groups (adults or children). Meta-analyses were executed in the groups and
subgroups with enough articles, using Review Manager
[16].
In subgroups with only one article, the
significance of the results was assessed.
RESULTS
Six hundred and sisteen articles were obtained from the literature search. They were analyzed in two
steps: 168 were selected in the first step and 17 were included in the data extraction phase ( [17-33]
figure 1). The agreement in the article selection phase was measured: mean kappa of 0.4215
(SD=0.22), with a mean kappa ratio of 0.55 (SD=0.30) in the first step, and mean kappa of 0.3509
(SD=0.24), with a mean kappa ratio of 0.46 (SD=0.31) in the second step (more information in
appendix 1).
Data was not available in 5 articles. From the remaining 17, only 6
[19,22,25,29,33]
were included in the
meta-analyses, those with mean as summary measure (figure 1). Although they presented the
correct results, 2 articles were excluded from the meta-analysis: Taylor et al
[31]
presented values
grouped by gender and Kovesi et al [26] had an SD similar to the mean, which could alter the results.
Results of data extraction are shown in table 1. From the 22 articles, 2
[26,27]
measured FeNO values
in individuals with atopy, 9 in those with allergic rhinitis[17-25] and 6 in the presence of both conditions
[27-33].
In those performed in subjects with allergic rhinitis, 4 measured FeNO values in children (<18
years), 10 in adults and one in both age groups. The last one was considered as performed in adults
for meta-analysis purposes (mean age was higher than 18). In atopic group 3 measures were done in
children and 5 in adults. The distribution of condition assessment between articles is shown in figure
2.
13
14
12
10
10
8
Medical
Diagnosis
5
6
4
1
Questionary/Sel
f Reported
Skin Prick Test
or Total IgE
2
0
Atopy
Allergic
Rhinitis
Figure 2. Method of condition assessment.
Qualitative analysis of data demonstrated that in all articles FeNO had a tendency for elevation in the
presence of the conditions.
Six articles were included in the meta-analyses, with analyses performed in different age groups as
shown in figure 3. In articles assessing atopy, meta-analysis showed a higher mean of FeNO of
10.00 (95%CI: 8.55-11.45) in atopic groups, with an I2 of 90% (fig. 4). In the article performed in
children the mean raise was 11.10 (95% CI: 9.13-13.07) and in the one performed in adults this
increase was of 9.50 (95% CI: 9.07-9.93).
Meta-analysis in the allergic rhinitis group exhibited a mean FeNO elevation of 13.84 (95% CI: 10.0817.60), with an I2 of 96%. In articles performed in adults, FeNO had a mean increase of 12.25 (95%
CI: 8.07-16.43), with an I2 of 97% (fig. 5). From measures performed in children, the mean raise was
17.45 (95% CI: 14.14-20.76), with an I2 of 0% (fig. 6). In all meta-analyses the differences were
statistically significant.
Author,
Year
Mean Age (minmax)
n of
healthy
n of
Allergic
Rhinitis
n of
atopic
FeNO –
healthy
Adults
18-55
14
18
-
Adults
Healthy: 27.5 ±
3.32
AR: 34.9 ± 2.76
*
Healthy: 28.6±2.9
AR: 33.0±1.7
*
10
14
-
40 ppb
(median)
12.6 ± 2.01
ppb*
10
38
-
30
40
-
opulation
Sample
Selection
Methods
Smoking
Habits
Factors
Studied
Allergic
Rhinitis
Assessment
Atopy Assessment
Age
Group
Allergic
Rhinitis
Allergic
Rhinitis
Medical
Diagnosis
Medical
Diagnosis
Skin Prick Test
Skin Prick Test
Adults
Aronsson et
al, 2005 [17]
Prieto et al,
2008[18]
Hospital patients
Not described
No
Voluntary from two other
studies
Consecutive
No
Prieto et al,
2002
Authors’ outpatient Allergy
Clinic and volunteers
Consecutive
No
Allergic
Rhinitis
Medical
Diagnosis
Skin Prick Test
General Population
Consecutive
No
Allergic
Rhinitis
Medical
Diagnosis
Skin Prick Test
[19]
FeNO –
atopic
35 ppb
-
30.2 ± 3.72
ppb*
-
11.2 (531,5)ppb
(mean (minmax))
9.5 (8.0-12.0)
ppb**
33.1 (5.7108.5)ppb
-
20.5 (12.533) ppb**
-
Muller et
al, 2005[21]
3 individuals
Consecutive
Not Stated
Allergic
Rhinitis
Not Described
-
Adults
Healthy: 18±5.9
AR: 32,8±7.2
*
No information
1
1
-
11.1 ppb
23.5ppb
-
Hung et al,
2007[22]
Patients from Tri-Service
General Hospital
Consecutive
Not Stated
Allergic
Rhinitis
Medical
Diagnosis
Skin Prick Test
Specific IgE
Child
5-14
12
45
-
9.44 ± 3.97
ppb*
24.68 ±
19.18 ppb*
-
Cibella et
al, 2008[23]
Children from eight schools
in Palermo
Random
Not Stated
Allergic
Rhinitis
Self-reported
-
Child
4-10
132
157
-
13.1 (3.071.0) ppb***
19.1 (5.892.5) ppb***
-
Razi et al,
2005[24]
Outpatients
Random
Not Stated
Allergic
Rhinitis
Self-reported
-
Child
7-14
17
57
-
12.3 (8.7521.2) ppb***
28.2 (20.647.25) ppb
-
Rolla et al,
2007[25]
Patients referred to
Outpatients Allergic Clinic
Consecutive
No
Allergic
Rhinitis
Self-reported
Skin Prick Test
Child Healthy: 41 (13-65)
and
AR: 30 (11-75)
#
Adults
30
38
-
13.5 ± 2.7
ppb*
24.5 ± 3.32
ppb*
-
Tanou et al,
2009
Adults
##
FeNO –
Allergic
Rhinitis
[20]
##
##
##
Kovesi et
al, 2008[26]
School Chidren
Consecutive
No
Atopy
-
Skin Prick Test
Child
10.8 (9.1-12.7)
657
-
253
14.0 ± 13.4
ppb*
-
18.1 ± 18
ppb*
Martins et
al, 2008[27]
Four primary schools in
Viseu
Consecutive
Not Stated
Atopy
-
Skin Prick Test;
Questionary/Clinical
Assessment
Child
6,7-8,8
(95%CI)
33
-
21
10 (8.5-12.25)
ppb***
-
28 (12.2537.25)
ppb***
Ching et al,
2005[28]
First Year Medical Students
at Nacional University of
Singapore
Consecutive
No
Atopy and
Allergic
Rhinitis
Medical
Diagnosis
Skin Prick Test;
Questionary/Clinical
Assessment
Adults
19.6 (18-27)
11
47
34
15.7 (11.723.8) ppb***
49.4 (30.484.3) ppb***
38.4 (16.749.2) ppb***
Dressel H
et al,
2008[29]
Patients from preemployment examinations
and occupational preventive
medical checkups
Consecutive
No
Atopy and
Allergic
Rhinitis
Medical
Diagnosis
Questionary/Clinical
Assessment
Adults
34.5 ±13*
405
193
119
17.8 ± 1.78
ppb*
26.4 ± 2.1
ppb*
27.3 ± 2.16
ppb*
Rouhos et
al, 2007[30]
General Population
Random
No
Atopy and
Allergic
Rhinitis
Medical
Diagnosis
Skin Prick Test;
Questionary/Clinical
Assessment
Adults
26-65
73
10
32
14 (2.1-49.8)
ppb**
23 (11.643.6) ppb**
17.5 (6.970.2 ppb)**
Taylor et
al, 2007[31]
32-year old individuals born
in Dunedin
Consecutive
No
Atopy and
Allergic
Rhinitis
Medical
Diagnosis
Skin Prick Test;
Questionary/Clinical
Assessment
Adults
32
(mean)
401
349
486
14,9 ppb
(mean)
Men:
24.8±2.04
Women:
15.6±0.77
ppb
*
Men:
24±1.63
Women:
16.1±0.97
ppb
*
Process workers in the
bleaching departments of
three pulp mills and from two
adjacent paper mills
Patients attended in
Hervás et
Department of Pediatric
al, 2008[33]
Allergy of Elche General
University Hospital
Consecutive
No
Atopy and
Allergic
Rhinitis
Medical
Diagnosis
Specific IgE;
Questionary/Clinical
Assessment
Adults
41-45
137
27
33
15.8 (11,4821,4) ppb ***
31 (16.050.5) ppb***
16.5 (11.327.6) ppb***
Consecutive
No
Atopy and
Allergic
Rhinitis
Self-reported
Skin Prick Test
Child
Healthy: 9.5 (6-16)
AR: 12.1 (7-15)
Atopic: 10 (7-15)
15
25
25
7.9 ± 1.2 ppb*
26.3 ± 7.73
ppb*
19 ± 3.7
ppb*
Welsh L. et
al, 2004[32]
#
#
##
##
#
Table 1 Articles included and its characteristics. Values indicated as: *mean ± SD; **median (min-max);
***median (IQ range); #mean (min-max); ##min-max, otherwise indicated. (AR: allergic rhinitis)
1: Child
Atopy: 2 Articles
1: Adults
2 Child
Allergic Rhinitis:
5 Articles
3: Adults
Figure 3. Articles used in meta-analysis: subgroups of articles based in age groups.
Figure 4. Meta analysis performed in the atopic group with the forest plot
Figure 5 Meta analysis performed in the adult subgroup of allergic rhinitic group with the forest plot
Figure 6. Meta analysis performed in the child subgroup of allergic rhinitic group with the forest plot
616 Articles
1st Selection
Phase: Reading
Titles and
Abstracts
Exclusion Criteria:
- Not talk about nitric oxide, or FeNO or
similar or ways of measure them (19.8%)
- Not Talk about atopy or similar or allergic
rhinitis or way of diagnose them (12,2%)
- Not being performed in humans. (12.7%)
- Not use original data.(31.8%)
128
Included
358
Excluded
130
Divergences
40
Included
90
Excluded
2nd Selection
Phase: Reading
Full Texts
Exclusion Criteria:
- First phase criteria.(32.9%)
- FeNO not measured in an online way.
(26.6%)
- FeNO not measured or measured in
individuals with confounding factors (25.6%)
- Absence of comparable groups. (8.0%)
17
Included
94
Excluded
3 Included
33
Divergences
22 Full Text not
available
30
Excluded
E-mail sent to
the authors
11
Answers
2 Included
Variables extracted:
- Atopy Assessment
- Population
- Smoking Habits
- Age Group
- Number of participants
- Number of atopy; allergic rhinitis; heathy
- Article conclusion about condition influence on FeNO
9
Excluded
Data Extraction
and
Analisys
22 Articles
8 with mean
as summary
measure
8 with median
as summary
measure
1 only with a
sample of 3
subjects
2
6 used in a
metaanalysis
Not used in
the meta
analysis
Figure 1. Workflow: articles analysis with the selection phase with the proper criteria (each article was excluded by, at
least, one criteria), data extraction with a variable’s summary and articles selection for inclusion in the meta-analysis.
DISCUSSION
This study concluded that FeNO values are raised in both individuals with atopy and with allergic
rhinitis. Qualitative analysis showed a tendency for high FeNO values in the presence of the
conditions (in the absence of asthma and in comparison with healthy controls) in all studies with
online measurements (according to ATS/ERS guidelines), the ones used in clinical practice. Metaanalysis demonstrate the elevation was significant (p<0.05) in both conditions, even in different age
groups.
A methodology based in an online data base and forms eliminated problems of cross information and
increased the efficiency, facilitating the definition of variables and the justification of all steps and
decisions. During the process, articles with no online full texts available were requested from their
authors, and the same was done to those without numeric data presented.
Studies in the past showed that atopy can by itself be responsible for FeNO raise even if the subjects
had another condition
[34]
. This study observed significant differences in FeNO values of individuals
with atopy when compared to healthy ones. These differences were similar to those observed in the
presence of allergic rhinitis, which raised the possibility that the elevation was due to the atopic
condition and not rhinitis. A study comparing allergic and non-allergic rhinitis influences in FeNO
values may clear this point.
In our study five articles were excluded due to lack of numeric values besides graphics. With
exception of the meta-analysis studying the effects of atopy in children’s FeNO values, all the others
had high heterogeneity values,
Meta-analyses showed that in all studies’ populations, FeNO values are raised in the presence of
atopy or allergic rhinitis, independently of subjects’ characteristics. Having different age groups in
comparison may explain the high heterogeneity observed in the meta-analysis; the heterogeneity
reduction observed when FeNO values variations were only analyzed in allergic rhinitis children
supports this. Other justifications for the high I2 is the diversity on the reliabiliy of the methods used to
assess atopy and allergic rhinitis, the low number of articles in each meta-analysis group and
subgroup and the different population provenience: samples extracted from a clinical environment
have a higher probability of having their condition controlled while the opposite is true for patients
recruited from different environments, what can influence the values.
Past research observed that FeNO values in allergic rhinitis patients differ according with the phase
of the pollen season
[18].
This must be taken into account in the interpretation of the meta-analyses’
high I2. Although all the articles which provided this information had agreeing results (elevated FeNO
values), it is important to assess how the time of measurement in relation to the pollen season can
modify them.
FeNO is nowadays used in asthma diagnosis. As demonstrated, its values are elevated in atopic
conditions, although in children its reliability is still a matter of discussion
results, Kovesi et al
[26]
[35].
In agreement with our
showed that, in children, FeNO is raised in allergic conditions, which was
confirmed by Dressel et al
[7]
in adults. Although no study showed a decrease in these values, Welsh
et al REF concluded that these differences were not significant; our meta-analysis, however, showed
that the difference had statistical significance (p<0.05). In allergic rhinitis condition the mean addition
value of patients corroborated data in the area [35].
In this meta-analysis, the influence of atopy and allergic rhinitis in FeNO values was measured,
corroborating the existing notion that the interpretation of this parameter must take into account comorbidities. Further studies are needed to measure the influence of other factors that influence FeNO
and their relation, exploring our conclusions and trying to reach new other. Also needed is a higher
level of concordance in data presentation between the different studies and new meta-analyses are
needed in the future, further exploring these influences.
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[32] Olin AC; Alving K; Torén K. Exhaled nitric oxide: relation to sensitization and respiratory
symptoms. Clin Exp Allergy. 2004
[33] Hervás, D; Milan, J; Garde, J.; Differences in exhaled nitric oxide in atopic children.
[34] Asch, Charlotte; Walter, A.F.; Balemans. Atopic disease and exhaled nitric oxide in an
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asthma in school children, Respir Med. 2006
Appendix 1
Query Search
To seek the query that will be used a series of trial searches were performed, the most relevant of
which are as follows (table 1, 2 and 3):
A
B
C
D
E
F
G
H
I
J
K
L
M
Search terms
Exhaled nitric oxide
Nitric Oxide
FeNO
eNO
Allergic
Rhinitis
“Allergic rhinitis”
Atop*
“Skin prick test”
“Prick test”
“Immunoglobin E”
“Ig E”
“Specific Ig”
Search Query
1
2
3
4
5
6
Query
1
2
3
4
5
6
Key
(A or B or C or D) and F
(A or B or C or D) and E and F
(A or B or C or D) and G
(A or B or C or D) and (F or I or J or K or L or M)
(A or B or C or D) and (G or I or J or K or L or M)
(A or B or C or D) and (G or F or H or I or J or K or L or M)
Table 2 – Query
Table 1 – Search Terms
Results
PubMed
With Clinical Query
(diagnosis and
Without Clinical Query
sensitive)
45
103
48
167
45
153
54
123
56
178
93
264
Scopus (with date of
publication
restrictions)
ISI
173
367
328
203
364
498
12
89
69
156
123
210
Table 3 – Results
After the trial searched, the elected search query was number 6:
(FeNO or eNO or exhaled nitric oxide or nitric oxide) and (“allergic rhinitis” or rhinitis or atop* or “skin
prick test” or “prick test” or “specific ig” or “ig e” or “immunoglobin e”)
Appendix 2
Agreement Study
In the first selection phase the mean proportion of agreement in the “Inclusion” answer was 0.4401, in
the “Exclusion” 0.7118. The mean kappa value was 0.4215 (SD=0.22), with a mean kappa ratio of
0.55 (SD=0.30), what lead to the conclusion that exclusion criteria were well applied, with
discordance being higher in article’s inclusion. In the second step the mean proportion of agreement
in the “Inclusion” answer was 0.3689, in the “Exclusion” 0.7066; the mean kappa value was 0.3509
(SD=0.24), with a mean kappa ratio of 0.46 (SD=0.31), leading to the same conclusion
Selection Phase
For the first articles’ distribution were made twenty-two groups of 28 articles, and these were
randomized twice: in the first time which each of the 11 reviewers was assigned 2 groups, and the
second one, with two more groups being attributed (paying attention not to repeat the articles). So,
the articles were double read. Reviewer’s opinion was obtained applying to them exclusion criteria,
such as: “It doesn't talks about nitric oxide or FENO or similar or values or ways of measure them”; “It
doesn't talks about atopy or similar or allergic rhinitis or similar or ways of diagnose them”; “It is not
performed in humans” and “It doesn’t use original data” (articles that used secondary data). This
criteria was contained in a Google Docs’ form, from which information was collected. Divergences
were discussed and, if they persist a third reviewer was required. The second selection phase, based
in full-text reading, was again performed in a form, and, four other new relevant exclusion criteria
were now added. The choice of these criteria was due to several facts: in clinical practice, FeNO
measurements used are only online ones, and, due to this, only studies with online measurements
were included, otherwise our goal of reaching values for clinical use would be compromised; articles
that didn’t performed FeNO measurements were not interesting for our study and they are rejected
too; if there is an absence of control groups for comparison of values (like healthy or non allergic
rhinitis ones), the summary measures couldn’t be performed and article was not included; in the end,
if the article measure nitric oxide in individuals with confounding factors that can alter its values, such
as asthma or other illnesses, it was not used. In this phase divergences in reviewers opinion was
solved only by discussion. 22 articles had no full-text available and e-mail was sent to the authors
asking for it.
Data Extraction
After article selection data was extracted, based in some different variables, many of them reflecting
our aim of, in the final conclusions, have no other interferences in FeNO values, rather than those
which are due to conditions studied. Variables extracted were, apart for the normal ones identifying
the article: atopy assessment (very important to know the reliability of values obtained), population
from where the sample was obtained, smoking habits and age group (depending on this, some
variations can be explained
[6] [7]),
number of participants and number of different ill groups
contemplated and FeNO’s unit and values in the different groups studied. If the article concluded
anything about influence of atopy or allergic rhinitis in exhaled NO values it was too resisted