10.14639/0392-100X-N2634
The goal of this meta-analysis was to study nasal nitric oxide (nNO) measurements in allergic rhinitis (AR) and non-allergic rhinitis (non-AR). The protocol was registered with PROSPERO (no: CRD4202124828). Electronic databases from PubMed, Google Scholar, Scopus, Web of Science, and Cochrane were all thoroughly searched and studies were chosen based on the qualifying requirements. The quality of the studies was evaluated by Joanna Briggs Institute evaluation tools, and publication bias using funnel plots. The metaanalysis included 18 studies, whereas the systematic review included 20 studies, totaling 3097 participants (1581 AR, 458 non-AR, and 1058 healthy/control). Patients with AR had significantly greater nNO levels than the control group, although this did not change significantly before or after treatment. AR patients had significantly greater nNO levels than non-AR patients, but there was no significant difference between non-AR patients and healthy controls. Nineteen of the studies were of high quality and the remaining one was of moderate quality. nNO measurement has a promising role in the management of AR and non-AR patients, but more investigations are needed to document clinical benefits.
text/xml
1827-675X
2634
en
Baharudin Abdullah
http://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
bronchial asthma
Nasal nitric oxide measurement in allergic rhinitis and non-allergic rhinitis: a meta-analysis
Text.Serial.Journal
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Rhinology
2024-04-22
2023-05-04
2024-04-23
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100-112
1
Baharudin Abdullah
2024/04/22
10.14639/0392-100X-N2634
100
Department of Otorhinolaryngology-Head and Neck Surgery, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia. Corrisponding author - profbaha@gmail.com 
1827-675X
bronchial asthma
en
112
Nasal nitric oxide measurement in allergic rhinitis and non-allergic rhinitis: a meta-analysis
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ACTA OTORHINOLARYNGOLOGICA ITALICA 2024;44:100-112; doi: 10.14639/0392-100X-N2634




Rhinology


Nasal nitric oxide measurement in allergic rhinitis
and non-allergic rhinitis: a meta-analysis
Ahmad Faiz Dahlan1, Md Asiful Islam2, Norasnieda Md Shukri1, Baharudin Abdullah1
1
 Department of Otorhinolaryngology-Head and Neck Surgery, School of Medical Sciences, Universiti Sains Malaysia,
Kubang Kerian, Kelantan, Malaysia; 2 WHO Collaborating Centre for Global Women’s Health, Institute of Metabolism and Systems
Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK


SUMMARY
The goal of this meta-analysis was to study nasal nitric oxide (nNO) measurements in al-
lergic rhinitis (AR) and non-allergic rhinitis (non-AR). The protocol was registered with
PROSPERO (no: CRD4202124828). Electronic databases from PubMed, Google Scholar,
Scopus, Web of Science, and Cochrane were all thoroughly searched and studies were
chosen based on the qualifying requirements. The quality of the studies was evaluated by
Joanna Briggs Institute evaluation tools, and publication bias using funnel plots. The meta-
analysis included 18 studies, whereas the systematic review included 20 studies, totaling
3097 participants (1581 AR, 458 non-AR, and 1058 healthy/control). Patients with AR
had significantly greater nNO levels than the control group, although this did not change
significantly before or after treatment. AR patients had significantly greater nNO levels
than non-AR patients, but there was no significant difference between non-AR patients and
healthy controls. Nineteen of the studies were of high quality and the remaining one was
of moderate quality. nNO measurement has a promising role in the management of AR and
non-AR patients, but more investigations are needed to document clinical benefits.
KEY WORDS: allergic rhinitis, non-allergic rhinitis, nitric oxide, nasal nitric oxide,
fractional exhaled nitric oxide, bronchial asthma



Introduction
Allergic rhinitis (AR) is characterised as inflammation of the nasal mucosa                    Received: May 4, 2023
brought on by type 2 helper T (Th2) cells 1. Due to immunoglobulin (Ig)E-                      Accepted: December 30, 2023
mediated reactions (type 1 hypersensitivity) to inhaled allergens, AR results
                                                                                               Correspondence
in sneezing, nasal pruritus, nasal obstruction, and primarily clear nasal dis-                 Baharudin Abdullah
charge. Most symptoms start to show up within minutes and can linger for                       E-mail: baharudin@usm.my; profbaha@gmail.com
hours. When AR affects children, it has a negative impact on their physical,
social, and psychological well-being, which indirectly affects parents and/or                    How to cite this article: Dahlan AF, Islam
other family members 2. AR can disrupt sleep and increase everyday weari-                        MA, Shukri NM, et al. Nasal nitric oxide
                                                                                                 measurement in allergic rhinitis and non-al-
ness, which can impair academic and professional performance 3. Clinical and                     lergic rhinitis: a meta-analysis. Acta Otorhi-
nasoendoscopic examination, and evidence of sensitisation – measured either                      nolaryngol Ital 2024;44:100-112. https://doi.
by the presence of allergen-specific IgE in serum or by positive skin prick                      org/10.14639/0392-100X-N2634
tests (wheal and flare responses to allergen extracts) – are used to make the
                                                                                               © Società Italiana di Otorinolaringoiatria
diagnosis of AR 4. Nitric oxide (NO) is an important element in the airways. It                e Chirurgia Cervico-Facciale
governs bronchial muscle tone, blood flow, and immunological response in the
lower airways, as well as cilia motility and defence mechanisms in the upper                                  OPEN ACCESS
airways 5.                                                                                     This is an open access article distributed in accordance with
                                                                                               the CC-BY-NC-ND (Creative Commons Attribution-Non-
Nasal NO (nNO) levels associate well with inflammatory biomarkers such as                      Commercial-NoDerivatives 4.0 International) license. The
eosinophil and eosinophil cationic protein levels and constitute a low-cost,                   article can be used by giving appropriate credit and mentio-
                                                                                               ning the license, but only for non-commercial purposes and
non-invasive technique to identify airway inflammation 6. nNO measurement                      only in the original version. For further information: https://
is a validated test that has been shown to be effective in the diagnosis and                   creativecommons.org/licenses/by-nc-nd/4.0/deed.en




100
                                                                                       nNO in allergic rhinitis and non-allergic rhinitis




monitoring of asthma, as well as having a potential role in     for using the “Advanced” and “Expert” search modes, to-
the management of AR.                                           gether with the Boolean logical operators (‘AND’ & ‘OR’)
Airway NO levels are measured using various parameters          (Supplementary Table I). To ensure a thorough search, the
such as oral fractional exhaled NO (FeNO), nasal FeNO,          references of the studies included were also examined. Du-
and nNO. While oral FeNO is typically prescribed for bron-      plicate studies were managed and filtered using EndNote
chial asthma, nasal FeNO and nNO have also been sug-            X8 software.
gested for AR patients 7. When the measurement is taken
through nasal exhalation, it is referred to as nasal FeNO. It   Study selection
is termed as nNO if it is acquired through transnasal flow in   A literature search was carried out independently by two
series. nNO levels are typically measured by a single expe-     authors (AFD and BA) by first screening the study’s title
rienced operator in accordance with the American Thoracic       and abstract, then retrieving the full texts of any matching
Society/European Respiratory Society (ATS/ERS) stand-           papers that met the inclusion requirements. All age groups
ards 7. Parts per billion (ppb) are the units of measurement.   with a physician-confirmed diagnosis of AR and non-AR
Aspiration at constant flow rate from one naris with gas        fulfilled the inclusion criteria. Excluded studies included
entrained via the other naris (transnasal flow in series) is    bronchial asthma research, review articles, case studies,
the currently advised technique for measuring nNO 7. This       non-human studies, views, and viewpoints. Disagreements
technique measures nNO in isolation from the lower res-         over inclusion were discussed and resolved (consensus be-
piratory tract and is the most widely used and most thor-       tween two authors, BA and MAI).
oughly validated. To prevent nNO leakage through the pos-       All studies examining nNO levels in AR and non-AR pa-
terior velopharyngeal gap, the velum must be closed. The        tients with controls, as well as pre- and post-treatment,
preferred technique has been determined to be slow oral         were considered. The information retrieved included the
exhalation against a resistance of at least 10 cm H20 since     nNO analyser, sampling technique, sample rate, and diag-
it has been demonstrated to consistently shut the velum 7.      nostic criteria. Studies were excluded if any of the follow-
The measurement of NO levels as oral FeNO, nasal FeNO,          ing were found: (1) number of AR patients was less than
and nNO differs, and thus a consistent approach is required     10; (2) the procedure of nNO measurement did not follow
to avoid misinterpretation. We conducted a systematic re-       the ATS/ERS Recommendations for Standardized Proce-
view and meta-analysis to evaluate the use of nNO meas-         dures for the Online and Offline Measurement of Exhaled
urements in AR and non-AR patients.                             Lower Respiratory Nitric Oxide and Nasal Nitric Oxide,
                                                                2005 7; and (3) AR diagnosis did not meet criteria described
                                                                in the Allergic Rhinitis and its Impact on Asthma (ARIA)
Methods
                                                                guidelines 9.
Reporting guidelines and protocol registration
The systematic review and meta-analysis were conduct-           Data extraction
ed according to the protocol registered in PROSPERO             The data from the studies included was accessed indepen-
(CRD42021248288). The updated guideline of preferred            dently by two authors (AFD and MAI). The essential data
reporting items for systematic reviews and meta-analyses        and information were obtained from each qualified study and
(PRISMA) served as the framework for the methodology            entered into a preset Excel spreadsheet. The following infor-
and reporting 8.                                                mation was collected from the studies chosen: type of study,
                                                                country, number of patients, number of controls, age of par-
Criteria for eligibility                                        ticipants, diagnosis, analyser used to detect nNO, and last ob-
The search was done to find relevant studies that looked        servation of each study. A consensus was reached among the
at nNO levels in individuals with AR and non-AR in both         authors regarding any discrepancies, ambiguities, or missing
the paediatric and adult age without limiting them to any       data. The corresponding or first author of the relevant studies
particular gender or race.                                      was emailed for clarification if the issue persisted.

Literature search                                               Quality assessment and publication bias
PubMed, Google Scholar, Scopus, Web of Science, and             The critical assessment tools developed by the Joanna
Cochrane were screened, with the final search performed         Briggs Institute were used to assess the quality of the in-
on August 24, 2022, and no language constraints. The terms      cluded studies. The studies were classified as poor qual-
“allergic rhinitis”, “non-allergic rhinitis”, “exhaled nitric   ity (high risk of bias), moderate quality (moderate risk of
oxide”, and “nasal nitric oxide” were specifically searched     bias), or high quality (low risk of bias) if the overall score



                                                                                                                                   101
A.F. Dahlan et al.




was 50 percent, 50-70 percent, or > 70 percent10,11. A publi-
cation bias evaluation using a funnel plot would be carried
out if there were 10 or more studies.

Data analysis
Parts per billion (ppb) was used as the standard for all nNO
level measurement units. The nNO levels were evaluated
using mean differences (MDs) and their corresponding
95% confidence intervals (CI). The random-effects model
and the I2 statistic were employed to measure trial hetero-
geneity (I2 > 75% indicating significant heterogeneity). The
significance of the heterogeneity test was evaluated using
the Cochran’s Q test. A sensitivity analysis was also car-
ried out to assess the accuracy of the findings and possible
sources of heterogeneity. All analyses were completed us-
ing RevMan software (version 5.3.5). A p value of 0.05 or
less was considered statistically significant.

Results
Study selection
561 articles were initially identified from the five databas-
es (Fig. 1). Following the removal of 229 duplicates and
another 32 studies (non-human subjects, review articles,
case reports, editorials, and comments), 267 studies were
excluded from the remaining articles based on title and/or            Figure 1. PRISMA flow-chart depicting the study selection process.
abstract evaluation, as they did not meet the criteria. Fi-
nally, the meta-analysis comprised 18 studies 6,12-21,24-30 and
the systematic review included 20 studies 6,12-30.                    In seven studies 12,13,17,18,21,23,24, patients were not given in-
                                                                      tranasal corticosteroids or oral antihistamines for their AR;
Characteristics of the included studies                               in three studies 6,14,30, a combination of oral antihistamines
All studies measured the nNO levels in AR, non-AR and                 and intranasal corticosteroids with or without a leukotriene
healthy (control) individuals, with a total of 3097 par-              receptor antagonist was given; two studies 27,29 used only
ticipants (1581 AR, 458 non-AR, 1058 healthy/control).                oral antihistamines; one study 28 used sublingual immuno-
The investigations were done in different nations, includ-            therapy; one study 25 used subcutaneous immunotherapy;
ing China (n = 8), Sweden (n = 3), Korea (n = 1), Finland             six studies did not provide this information 15,16,19,20,22,26. The
(n = 1), Taiwan (n = 1), Vietnam (n = 1), Czech Republic              length of treatment varied, ranging from two weeks to a
(n = 1), USA (n = 1), Turkey (n = 1), Italy (n = 1) and               year. AR with bronchial asthma was included in three stud-
Greece (n = 1).                                                       ies 13,18,26, while AR with nasal polyps was included in one
Except for three cross-sectional studies 26-28, all papers were       study1 8. Table I summarises the characteristics of the stud-
case control studies 6,12-25,29,30. The NO analysers used were        ies included.
made by Sievers 280i, NIOX, NIOX MINO, HypAir, Ana-
lyser CDL 88, Nano Coulomb Breath Analyzer CA2122.                    Outcomes
Apart for two studies 15,21, which employed chemilumines-
                                                                      A. nNO levels in AR patients
cence analysers, all studies 6,12-14,16-20,22-30 used electrochemi-
                                                                      Patients with AR were compared to controls in 13 stud-
cal analysers. Conventional clinical criteria, including
                                                                      ies 6,12-21,24,25. The nNO levels were substantially greater in
symptoms, examination, and allergy testing, were used to
                                                                      AR patients than healthy subjects (MD: 296.18, 95% CI:
confirm AR diagnosis in accordance with guidelines 9. Skin
                                                                      118.18 to 474.17; p = 0.001) (Fig. 2A).
prick testing and serum specific IgE were procedures em-
ployed for confirmatory allergy testing. Online measure-              B. nNO levels in pre- and post-treated patients
ment techniques were applied in all testing.                          Six studies 6,25,27-30 investigated nNO levels in AR patients



102
                                                                                                                      nNO in allergic rhinitis and non-allergic rhinitis




Table I. Main characteristics of the studies included.
 No.      Study       Country      No. of      Age (years)      Diagnosis      Type of AR     Severity   Comorbid     Analyser        Treatment            Outcomes
                                participants                      of AR                        of AR     condition
 1     Lee, 2012 15    Korea      AR: 35           AR:          Skin prick     Intermittent    Mild to      No          Sievers           NR               nNO levels
                                                22.7 ± 8.7         test            and         severe                  280i (Ge                        significantly higher
                                                                                persistent                             Analytical                      in AR compared to
                                                                                                                     Instruments,                             control
                                                                                                                       Colorado)
                                   C: 34            C:
                                               26.9 ± 11.0
 2     Hou, 2018 12    China      AR: 75           AR:          Serum IgE      Intermittent    Mild to      No          NIOX            None             Compared with
                                               36.2 ± 10.9     measurement         only        severe                 (Aerocrine                      controls, nNO levels
                                                                                                                      AB, Solna                         were significantly
                                                                                                                       Sweden)                        higher in AR patients
                                   C: 31            C:
                                               35.3 ± 12.1
 3     Suojalehto,    Finland     AR: 89           AR:             Skin            NR            NR          1.         NIOX            None           1.nNO levels were
        2014 18                                 32.9 ± 1.3      prick test,                              bronchial    (Aerocrine                         elevated in AR
                                                                serum IgE                                 asthma      AB, Solna                       compared to controls
                                                               measurement                                             Sweden)
                                Non-AR: 44     Non-AR: 33.2                                               2. nasal                                     2. nNO levels did
                                                  ± 1.5                                                    polyps                                      not differ between
                                                                                                                                                      non-AR and control
                                                                                                                                                      groups or between
                                                                                                                                                        non-AR and AR
                                                                                                                                                             groups
                                   C: 42       C: 33.5 ± 1.8
 4       Irander,     Sweden      AR: 18       AR: 18 ± NR      Skin prick     Intermittent     NR       Bronchial      NIOX            None          Higher levels of nNO
         2012 13                                                   test            and                    asthma      (Aerocrine                       were found in AR
                                                                                persistent                            AB, Solna                       compared to control
                                                                                                                       Sweden)
                                    C: 7        C: 18 ± NR
 5        Wen,        Taiwan      AR: 90       AR: 9.7 ± 2.4     Allergen      Persistent       NR          No       NIOX MINO            NR           Significantly higher
         2019 19                                                specific IgE     only                                (Aerocrine                        nNO levels and total
                                                                  testing                                             AB, Solna                         nasal resistance in
                                                                                                                      Sweden)                         children with AR than
                                                                                                                                                         normal children
                                   C: 79       C: 10.1 ± 1.9
 6     Kim, 2020 14   Vietnam     AR: 267          AR:          Skin prick     Persistent      Mild to      No          HypAir      Desloratadine         nNO levels of
                                               36.0 ± 17.0         test          only          severe                 (Medisoft,    combined with         persistent AR
                                                                                                                       Belgium)     montelukast, or   patients were higher
                                                                                                                                    with intranasal       than controls
                                                                                                                                      fluticasone
                                                                                                                                     propionate x
                                                                                                                                          6/12
                                  C: 234            C:
                                               37.0 ± 18.0
 7        Palm,       Sweden      AR: 18        AR: 32 (21-     Skin prick     Intermittent    Mild to      No          NIOX            None            Patients with AR
         2003 17                                    50)            test            only       moderate                (Aerocrine                        have higher and
                                                                                                                      AB, Solna                       larger interindividual
                                                                                                                       Sweden)                        spread in nNO levels
                                                                                                                                                      compared to controls
                                   C: 18       C: 30 (20-46)
 8     Maniscalco,    Sweden      AR: 15           AR:          Skin prick         NR           NR          No       NIOX MINO            NR            nNO levels were
        2008 16                                36.0 ± 13.9         test                                              (Aerocrine                       slightly higher in AR
                                                                                                                      AB, Solna                       compared to control
                                                                                                                      Sweden)                                 group
                                   C: 15       C: 27.9 ± 2.3

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A.F. Dahlan et al.




Table I. follows.
 No.      Study       Country       No. of      Age (years)      Diagnosis     Type of AR     Severity   Comorbid     Analyser        Treatment            Outcomes
                                 participants                      of AR                       of AR     condition
 9      Antosova,      Czech       AR: 50         AR: Men        Skin prick    Intermittent     NR          No       NIOX MINO            Oral         1. AR patients may
         2020 6       Republic                  42.5 ± 15.3,        test           only                              (Aerocrine      antihistamine    frequently have high
                                                  Women:                                                              AB, Solna     and intranasal         nNO values
                                                39.0 ± 10.9                                                           Sweden)       steroids x 3/52
                                    C: 50          C: Men                                                                                               2. No significant
                                                 21.3 ± 1.7,                                                                                           differences in nNO
                                                  Women:                                                                                              after three weeks of
                                                 21.0 ± 3.7                                                                                                 treatment
 10    Liu, 2015 20    China       AR: 30            NR          Skin prick        NR           NR          No       NIOX MINO            NR           1. nNO levels were
                                                                    test                                             (Aerocrine                        significantly higher
                                                                                                                      AB, Solna                        in children with AR
                                                                                                                      Sweden)                         compared to healthy
                                                                                                                                                             children
                                 Non-AR: 10
                                    C: 25                                                                                                              2. Non-AR children
                                                                                                                                                          had higher nNO
                                                                                                                                                       levels than healthy
                                                                                                                                                        children, although
                                                                                                                                                      the levels were lower
                                                                                                                                                         than AR children
 11      Makris,      Greece       AR: 26       AR: 28.4 (16-    Skin prick    Intermittent     NR          No       Analyser           None             nNO levels were
         2011 21                                     47)            test           only                               CDL 88                            increased during
                                                                                                                      sp (ECO                          pollen season only
                                                                                                                     MEDICS,                             in patients with
                                                                                                                     Duernten,                          bronchial hyper-
                                                                                                                     Sweden)                             responsiveness
                                    C: 15       C: 37.1 (31-
                                                    43)
 12    Ren, 2019 22    China       AR: 151       AR: 45 (18-     Skin prick        NR           NR          No       NIOX MINO            NR           1. nNO levels were
                                                     63)            test                                             (Aerocrine                        significantly higher
                                                                                                                      AB, Solna                        in AR patients than
                                                                                                                      Sweden)                             in healthy and
                                                                                                                                                      asymptomatic atopic
                                                                                                                                                             subjects
                                   Non-AR:       Non-AR: 47
                                     298          (19-64)
                                   C: 328       C: 45 (18-68)                                                                                          2. nNO levels were
                                                                                                                                                        not substantially
                                                                                                                                                       different in non-AR
                                                                                                                                                       patients compared
                                                                                                                                                        to AR or non-AR
                                                                                                                                                      patients compared to
                                                                                                                                                        normal subjects.
 13       Zhao,        China       AR: 60           AR:             Skin           NR           Mild,       No           Nano           None           The nNO in the AR
         2022 23                                 25.0 ± 6.3      prick test,                  moderate                Coulomb                          group was higher
                                                                 serum IgE                     severe                   Breath                          than in healthy
                                                                measurement                                           Analyzer                              people
                                                                                                                       CA2122
                                                                                                                       (Sunvou
                                                                                                                       Medical
                                                                                                                     Electronics,
                                                                                                                        China)
                                    C: 30       C: 27.0 ± 8.4




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104
                                                                                                                       nNO in allergic rhinitis and non-allergic rhinitis




Table I. follows.
 No.      Study        Country      No. of      Age (years)      Diagnosis     Type of AR     Severity    Comorbid     Analyser        Treatment            Outcomes
                                 participants                      of AR                       of AR      condition
 14    Li, 2021 24      China      AR: 30            AR:         Skin prick    Persistent        NR          No           Nano           None           The levels of nNO
                                                37.6 ± 14.76        test         only                                  Coulomb                          in AR group were
                                                                                                                         Breath                         higher than in the
                                                                                                                       Analyzer                           control group
                                                                                                                        CA2122
                                                                                                                        (Sunvou
                                                                                                                        Medical
                                                                                                                      Electronics,
                                                                                                                         China)
                                    C: 30            C:
                                                33.43 ± 16.2
 15       Wen,          China      AR: 120          AR:             Skin           NR         Moderate       No           Nano          SCIT Novo-      1. nNO levels were
         2023 25                                31.7 ± 10.6      prick test,                  to severe                Coulomb        Helisen Depot    higher in AR patients
                                                                 serum IgE                                               Breath       (NHD) allergen      than in controls
                                                                measurement                                            Analyzer           extracts
                                                                                                                        CA2122       (Allergopharma,
                                                                                                                        (Sunvou          Reinbek,
                                                                                                                        Medical        Germany) x 1
                                                                                                                      Electronics,          year
                                                                                                                         China)
                                    C: 40       C: 30.4 ± 7.6                                                                                             2. Higher nNO
                                                                                                                                                           is seen with
                                                                                                                                                           symptomatic
                                                                                                                                                          reduction after
                                                                                                                                                          subcutaneous
                                                                                                                                                             injections
                                                                                                                                                         immunotherapy
 16    Kalpaklioglu,   Turkey      Non-AR:       Non-AR: 28         Skin       Intermittent     Mild,     Bronchial   NIOX MINO            NR           AR had significantly
         2021 26                     106          (22-39)        prick test,       and        moderate-    asthma     (Aerocrine                         higher nNO levels
                                                                 serum IgE      persistent     severe                  AB, Solna                         compared to NAR
                                                                measurement                                            Sweden)                         (370 ppb vs 290 ppb
                                   AR: 337      AR: 25 (20-
                                                    33)
 17    Luo, 2021 27     China      AR: 61            AR:         Serum IgE         NR            NR          No           Nano       Oral loratadine      nNO values were
                                                 7.5 ± 2.18     measurement                                            Coulomb        for 3 weeks           higher after
                                                                                                                         Breath                         treatment. Possible
                                                                                                                       Analyzer                            reasons were:
                                                                                                                        CA2122
                                                                                                                        (Sunvou
                                                                                                                        Medical
                                                                                                                      Electronics,
                                                                                                                         China)
                                                                                                                                                       1. anti-inflammatory
                                                                                                                                                        drugs do not work
                                                                                                                                                         efficiently due to
                                                                                                                                                        reduced diffusion
                                                                                                                                                              capacity
                                                                                                                                                       2. airway remodeling
                                                                                                                                                        may interfere with
                                                                                                                                                             nNO levels
 18       Parisi,       Italy      AR: 34        AR: 10.1 ±         Skin       Persistent        NR          No       HypAir FeNO   House dust           Significant nNO
         2021 28                                     3.2         prick test,     only                                  (Medisoft, mite sublingual      value was reached
                                                                 serum IgE                                              Belgium)  immunotherapy         when the patients
                                                                measurement                                                           x 6/12            completed the 6
                                                                                                                                                       months of treatment



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                                                                                                                                                                       105
A.F. Dahlan et al.




Table I. follows.
 No.      Study       Country       No. of        Age (years)      Diagnosis      Type of AR     Severity     Comorbid       Analyser        Treatment             Outcomes
                                 participants                        of AR                        of AR       condition
                                                                                                                                              plus oral
                                                                                                                                           antihistamines,
                                                                                                                                             intranasal
                                                                                                                                           corticosteroids,
                                                                                                                                            montelukast
 19      Bautista,      USA         AR: 31        AR: 29 (13-      Skin prick     Persistent        NR            No          NIOX              Oral          Significant difference
         2011 29                                      45)             test          only                                    (Aerocrine     levocetirizine x      pre & post, and
                                                                                                                            AB, Solna           2/52             treatment with
                                                                                                                             Sweden)                                 placebo
                                     C: 31       C: 29 (13-45)
 20       Wang,         China       AR: 44       AR: 6.8 ± 2.3       Skin         Persistent       Mild,          No            Nano        Mometasone        Significant difference
         2017 30                                                  prick test,       only         moderate                    Coulomb        furoate alone      in nNO levels after
                                                                  serum IgE                       severe                       Breath      or mometasone            treatment
                                                                 measurement                                                 Analyzer          furoate
                                                                                                                              CA2122          combined
                                                                                                                              (Sunvou          with oral
                                                                                                                              Medical      antihistamine x
                                                                                                                            Electronics,        1/12
                                                                                                                               China)
                                     C: 49       C: 7.2 ± 1.9
AR: allergic rhinitis; non-AR: non-allergic rhinitis; C: control; nNO: nasal nitric oxide; IgE: immunoglobulin E; NR: not reported.



before and after treatment, but no studies for non-AR pa-                                   these two studies were excluded the MD became 25.87 ppb
tients were found. nNO levels in AR patients did not change                                 lower than the overall value (Supplementary Table IV). The
substantially before or after treatment (MD: 146.35, 95%                                    difference of nNO levels between the AR and control par-
CI: -16.28 to 308.97; p = 0.08) (Fig. 2B).                                                  ticipants, however, remained statistically significant.
C. nNO levels in non-AR patients
nNO levels in non-AR patients were compared to controls                                     Discussion
in two studies 18,20, and to AR patients in three studies 18,20,26.                         The use of FeNO as a measurement technique in bronchial
Compared to non-AR patients, AR patients had higher nNO                                     asthma has been demonstrated to have high accuracy re-
levels (MD: 78.06, 95% CI: 33.20 to 122.91; p < 0.001)                                      gardless of the type of instrument utilised 31. With such pre-
(Fig. 2C). There was no difference in nNO levels between                                    cision, it can be used as a screening and diagnostic tool for
non-AR patients and healthy controls (MD: 58.09, 95% CI:                                    the allergic airway condition. The NO analysis method for
-29.12 to 145.31; p = 0.19) (Fig. 2D).                                                      nNO in patients with AR, chronic rhinosinusitis, or primary
                                                                                            ciliary dyskinesia has been developed and evaluated.
Quality assessment and publication bias                                                     The current meta-analysis observed that nNO levels in AR
The quality assessment of the case-control studies can be                                   patients were considerably higher than in the control group.
seen in Supplementary Table II and the cross-sectional                                      There are two outlier studies with extraordinarily high nNO
studies in Supplementary Table III. Ninety-five percent                                     values. Due to the existence of numerous confounding factors
(n = 19) of the included studies were of high quality (low                                  that contribute to the formation or exacerbation of AR, such
risk of bias) and the remaining 5% (n = 1) were of moder-                                   as cigarette smoking, frequent exposure to allergens such as
ate quality (moderate risk of bias). The funnel plot revealed                               pollen, home dust mites, dog and cat hairs, and cockroaches,
the possibility of publication bias in estimating the mean                                  the level of nNO was exceedingly high in the study by Kim
difference of nNO levels between AR patients and controls,                                  et al. 14 even after treatment. Wen et al. 19 reported a very high
as well as nNO levels in AR patients before and after treat-                                nNO level since they included AR patients who had severe
ment (Supplementary Figure 1).                                                              sinusitis.
                                                                                            The concurrent occurrence of AR in asthma patients, known
Sensitivity analysis                                                                        as the one airway theory, is characterised by eosinophil in-
We determined that Kim et al. 14 and Wen et al. 19 were                                     flow, mast cell degranulation, and an increase in Th2-relat-
outlier studies using the leave-one-out method, and when                                    ed cytokine release from lymphocytes 32. AR patients with



106
                                                                                                                   nNO in allergic rhinitis and non-allergic rhinitis




A




B




C




D




Figure 2. Forest plot representing the (A) nNO levels between patients with allergic rhinitis and controls and (B) pre- and post-treatment; (C) allergic rhinitis and
non-allergic rhinitis and (D) non-allergic rhinitis vs controls.



                                                                                                                                                               107
A.F. Dahlan et al.




and without asthma are frequently evaluated for airway           there is no difference in nNO levels between non-AR and
hyper-responsiveness, spirometry, allergen skin testing,         controls. These results appear to indicate nNO levels would
total and specific IgE, and NO measurement. A study by           be effective in distinguishing non-AR from AR, but not in
Duong-Quy et al. 33 found that nasal FeNO levels were not        distinguishing non-AR from healthy people. The evalua-
substantially different between AR and AR-asthma partici-        tion of the efficacy of anti-inflammatory therapies is another
pants, but were significantly greater in AR and AR-asthma        use for nNO measurement; documenting the levels of nNO
subjects than in control subjects. This suggests that nasal      before and after treatment can be invaluable in determining
FeNO levels and AR symptoms in people with or without            how well each therapeutic approach works. However, this
asthma were substantially correlated. This finding implies       meta-analysis found that using nNO in AR patients to deter-
that NO measurement may be used as a tool in the manage-         mine therapeutic efficacy may not be helpful, and caution is
ment of AR when combined with clinical symptoms. Ad-             advised when interpreting the results. Similarly, it is unclear
ditionally, Nesic et al. 34 showed that nasal FeNO was very      whether monitoring therapy in non-AR patients with nNO
reliable in differentiating between AR patients and healthy      will be beneficial, given no studies have documented such
individuals. In light of this finding, the authors proposed      measurement. In addition to evaluating the measurement of
NO measurement as an objective and independent metric in         nNO in diagnosing non-AR patients and its significance in
the identification of AR patients with or without additional     monitoring therapeutic effectiveness, the results of this meta-
respiratory comorbidities like asthma.
                                                                 analysis support those of two earlier meta-analyses 41,42.
In another investigation, it was reported that the nNO lev-
els varied in accordance with the intensity of the clinical
                                                                 Limitations of the study
symptoms in people with seasonal AR during the pollen
                                                                 The findings from our study may have some limitations.
season 35. The increased production of nNO brought on
                                                                 The literature search was restricted to research reports, with
by airborne allergens (pollens, house dust mites, or cat or
                                                                 conference abstracts, review papers, case studies, non-hu-
dog hairs) is the reason for the greater levels of nNO in
                                                                 man studies, views, and viewpoints removed while the sub-
AR compared to healthy people. In comparison to FeNO
                                                                 group’s sample size was moderate, and several of the studies
levels in the lower airway, nNO levels in the upper airway
are significantly higher. The observation that nNO levels        used a variety of confounding variables that might influence
are significantly greater than FeNO may be due to the            the nNO levels. The inclusion of diverse types of AR pa-
high NO production by the sinus epithelium 36. Exhaled           tients with varying severity, AR patients with or without con-
nNO is generated not only by gradient diffusion from the         comitant diseases, and AR patients receiving therapy or not
sinuses, but also by NO produced by nasal mucosal mem-           are most likely contributing factors for the extremely high
branes (epithelium) and inflammatory cells (eosinophils)         heterogeneity among studies. Variability in the technique of
in response to iNOS overexpression 13,29,37,38. Thus, in pa-     measurement and the device used can impact the reliability
tients with AR, nNO measurement shows eosinophilic in-           and reproducibility of results. Lack of standardised proto-
flammation with a strong link to clinical symptoms and           cols for nNO measurement can hinder comparisons between
airway inflammation.                                             studies and limit the establishment of universal diagnostic
While nNO is more established in AR, its role in non-AR,         criteria. nNO may not predict treatment response uniformly
and especially in certain subtypes like vasomotor rhinitis, is   across all patients, and its role as a predictor of therapeutic
not as well-defined. In vasomotor rhinitis, there is evidence    outcomes remains an area of investigation.
of neurogenic dysregulation, contributing to nasal hyper-
reactivity and increased nasal congestion 39. In other cases,    Conclusions
the exact cause is unknown, leading to the term idiopathic
rhinitis. While the exact mechanisms can vary, some forms        The outcomes of this meta-analysis indicate that while nNO
of non-AR may involve nasal inflammation 40. NO measure-         measurement can discriminate between AR and healthy in-
ments may provide insights into the underlying pathophysi-       dividuals, it is unable to distinguish non-AR from healthy
ology and guide treatment strategies. Furthermore, nNO           individuals. Additionally, nNO measurement can identify
measurement can assist in differentiating between allergic       AR patients from non-AR individuals. Caution should be
and non-allergic forms of rhinitis. The measurement might        taken when interpreting nNO levels to monitor the efficacy
augment skin prick testing, which is the main clinical diag-     of treatment in AR patients. nNO measurement has a prom-
nostic tool to identify AR and non-AR 40. In the present me-     ising role in the management of AR and non-AR patients,
ta-analysis, we found that nNO differs between non-AR and        but more investigations are needed to document clinical
AR with the latter having higher nNO levels. Interestingly,      benefits.



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                                                                                                               nNO in allergic rhinitis and non-allergic rhinitis




Conflict of interest statement                                                  12
                                                                                     Hou J, Lou H, Wang Y, et al. Nasal ventilation is an important factor in
                                                                                     evaluating the diagnostic value of nasal nitric oxide in allergic rhinitis.
The authors declare no conflict of interest.                                         Int Forum Allergy Rhinol 2018;8:686-694. https://doi.org/10.1002/
                                                                                     alr.22087
Funding                                                                         13
                                                                                     Irander K, Palm JP, Borres MP, et al. Clara cell protein in nasal lav-
This research did not receive any specific grant from fund-                          age fluid and nasal nitric oxide − biomarkers with anti-inflammatory
ing agencies in the public, commercial, or not-for-profit                            properties in allergic rhinitis. Clin Mol Allergy 2012;10:4. https://doi.
                                                                                     org/10.1186/1476-7961-10-4
sectors.                                                                        14
                                                                                     Vo-Thi-Kim A, Van-Quang T, Nguyen-Thanh B, et al. The effect of
                                                                                     medical treatment on nasal exhaled nitric oxide (NO) in patients with
Author contributions                                                                 persistent allergic rhinitis: a randomized control study. Adv Med Sci
AFD, MAI, NMS, BA: made a substantial contribution to                                2020;65:182-188. https://doi.org/10.1016/j.advms.2019.12.004
the conception and design of the article, to the acquisition,
                                                                                15
                                                                                     Lee KJ, Cho SH, Lee SH, et al. Nasal and exhaled nitric oxide in
                                                                                     allergic rhinitis. Clin Exp Otorhinolaryngol 2012;5:228-233. https://
analysis and interpretation of data. All authors critically re-                      doi.org/10.3342/ceo.2012.5.4.228
vised the article and gave the final approval of the version                    16
                                                                                     Maniscalco M, de Laurentiis G, Weitzberg E, et al. Validation
to be published.                                                                     study of nasal nitric oxide measurements using a hand-held electro-
                                                                                     chemical analyser. Eur J Clin Invest 2008;38:197-200. https://doi.
                                                                                     org/10.1111/j.1365-2362.2008.01907.x
Ethical consideration                                                           17
                                                                                     Palm JP, Alving K, Lundberg JO. Characterization of airway
The systematic review and meta-analysis design of this ar-                           nitric oxide in allergic rhinitis: the effect of intranasal admin-
ticle does not require ethical approval from our institution.                        istration of L-NAME. Allergy 2003;58:885-892. https://doi.
This article does not involve generation of new data from                            org/10.1034/j.1398-9995-2003.00098.x
human or animal and no consent is necessary.
                                                                                18
                                                                                     Suojalehto H, Vehmas T, Lindstrom I, et al. Nasal nitric oxide is
                                                                                     dependent on sinus obstruction in allergic rhinitis. Laryngoscope
                                                                                     2014;124:E213-E218. https://doi.org/10.1002/lary.24590
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Table SI. Search strategies.
 Databases                                                                                          Search strategies
 PubMed                                (allergic rhinitis, non-allergic rhinitis, treatment [Title/Abstract]) AND (nasal nitric oxide[Title/Abstract] OR nNo[Title/Abstract])
 Scopus                                        TITLE-ABS (“allergic rhinitis”, “non-allergic rhinitis”, “treatment”) AND TITLE-ABS (“nasal nitric oxide” OR nNo)
 Web of Science                                              TI= (allergic rhinitis, non-allergic rhinitis, treatment) AND TI= (nasal nitric oxide OR nNo)
                                                   Indexes: SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, BKCI-S, BKCI-SSH, ESCI Timespan: all years
 Cochrane Library                                           (allergic rhinitis, non-allergic rhinitis, treatment) AND (nasal nitric oxide OR nNo): ti,ab,kw
 Google Scholar                                          All in title: (“allergic rhinitis”) (“non-allergic rhinitis”) (“treatment”) (“nasal nitric oxide” OR nNo)



Table SII. Quality assessment of the case-control studies.
 No.                       Study ID                                              Questions assessing included case-control studies                                     Yes (%)
                                                                   1         2        3         4         5        6         7         8        9         10
 1                              Lee, 2012   15
                                                                   Y         Y        Y         Y         Y        Y         Y         Y        U          Y              90

 2                             Hou, 2018 12                        Y         Y        Y         Y         Y        Y         Y         Y        U          Y              90

 3                          Suojalehto, 2014 18                    Y         Y        Y         Y         Y        Y         U         Y        Y          Y              80

 4                            Irander, 2012 13                     Y         Y        Y         Y         Y        N         N         Y        Y          Y              80

 5                             Wen, 2019 19                        Y         Y        Y         Y         Y        Y         Y         Y        U          Y              90

 6                             Kim, 2020 14                        Y         Y        Y         Y         Y        Y         U         Y        Y          Y              90

 7                             Palm, 2003 17                       Y         Y        Y         Y         Y        U         U         Y        Y          Y              80

 8                         Maniscalco, 2008 16                     Y         Y        Y         Y         Y        Y         N         Y        Y          Y              90

 9                           Antosova, 2020 6                      Y         Y        Y         Y         Y        U         U         Y        Y          Y              80

 10                             Liu, 2015 20                       Y         Y        Y         Y         Y        Y         U         Y        N          Y              80

 11                           Makris, 2011 21                      Y         Y        Y         Y         Y        U         U         Y        Y          Y              80

 12                            Ren, 2019 22                        Y         Y        Y         Y         Y        Y         Y         Y        U          Y              80

 13                              Li, 2021 24                       Y         Y        Y         Y         Y        U         U         Y        U          Y              70

 14                            Wen, 2023 25                        Y         Y        Y         Y         Y        U         U         Y        Y          Y              80

 15                            Zhao, 2022 23                       Y         Y        Y         Y         Y        Y         U         Y        Y          Y              90

 16                          Bautista, 2011 29                     Y         Y        Y         Y         Y        Y         Y         Y        U          Y              90

 17                           Wang, 2017 30                        Y         Y        Y         Y         Y        U         U         Y        Y          Y              80

1. Were the groups comparable other than the presence of disease in cases or the absence of disease in controls? 2. Were cases and controls matched appropriately? 3. Were the
same criteria used for identification of cases and controls? 4. Was exposure measured in a standard, valid and reliable way? 5. Was exposure measured in the same way for cases
and controls? 6. Were confounding factors identified? 7. Were strategies to deal with confounding factors stated? 8. Were outcomes assessed in a standard, valid and reliable way for
cases and controls? 9. Was the exposure period of interest long enough to be meaningful? 10. Was appropriate statistical analysis used? Y: yes; N: no; U: unclear.




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A.F. Dahlan et al.




Table SIII. Quality assessment of the cross-sectional studies.
 No.                              Study ID                                          Questions assessing included cross-sectional studies                               Yes (%)
                                                                            1           2          3          4           5          6           7         8
 1                               Kalpaklioglu, 2021 26                      Y           Y          Y          Y           U          U           Y         Y              60

 2                                    Luo, 2021 27                          Y           Y          Y          Y           Y          N           Y         Y              70

 3                                   Parisi, 2021 28                        Y           Y          Y          Y           Y          Y           Y         Y              80

1. Were the criteria for inclusion in the sample clearly defined? 2. Were the study subjects and the setting described in detail? 3. Was the exposure measured in a valid and reliable
way? 4. Were objective, standard criteria used for measurement of the condition? 5. Were confounding factors identified? 6. Were strategies to deal with confounding factors stated?
7. Were the outcomes measured in a valid and reliable way? 8. Was appropriate statistical analysis used? Y: yes; N: no; U: unclear.



Table SIV. Sensitivity analyses.
     Strategies of               MD [95% CI]                     Difference of MD        Overall effect            Number           Total number of            Heterogeneity
  sensitivity analyses                                           compared to the           (p value)              of studies          participants
                                                                    main result                                   analysed
                                                                                                                                                               I2        p value
 Excluding outlier studies      270.31 [170.37, 370.26]              25.87 lower            < 0.00001                11                    891               96%       < 0.00001



 Excluding small studies 390.09 [122.44, 657.74]                    93.91 higher              0.004                  10                   1392              100%       < 0.00001
 (n < 50)

MD: mean difference, CIs: confidence intervals.




 A                                                                                             B




Figure S1. Funnel plot showing potential presence of publication bias representing the (A) nNO levels between patients with allergic rhinitis and controls and
(B) pre- and post-treatment.




112
