Detection of local allergic rhinitis in children with chronic, difficult‐to‐treat, non‐allergic rhinitis using multiple nasal provocation tests

Abstract

Background
There is little evidence on the incidence and characteristics of local allergic rhinitis (LAR) in children. Most studies have included subjects with perennial rhinitis only, and results are based on the investigation of no more than three allergens per study. Our aim was to determine the proportion of children with LAR amongst children with chronic, difficult‐to‐treat, perennial or seasonal, rhinitis but no evidence of sensitization to aeroallergens, or other alternative diagnosis.

Methods
We performed multiple nasal provocation tests (M‐NPTs) with four locally relevant aeroallergens (Phleum pratense, Olea europea, Alternaria alternata, and Dermatophagoides pteronyssinus) in children with absence of aeroallergen sensitization, seen during a calendar year in a specialized rhinitis clinic. We additionally performed single NPT to children with allergic rhinitis (AR; positive control group). The result of the NPT was based on symptoms and acoustic rhinometry. Identification of nasal hyper‐reactivity (NHR) triggers was through a questionnaire.

Results
Local allergic rhinitis was confirmed in 29.2% (7/24) of the negative SPT/blood testing population. All but one of the children reacted to one allergen and one to two. All AR children had positive single NPT with results similar to the LAR. There were no differences in age at examination and rhinitis onset, gender distribution, family atopy, and past or current environment of residency, while the prevalence of reported NHR triggers was comparable amongst the three groups.

Conclusion
This is the first pediatric study where the seasonal or perennial rhinitis population was thoroughly tested for LAR against four aeroallergens. LAR is present in a considerable proportion of children with chronic, difficult‐to‐treat rhinitis and no sensitization to aeroallergens, and therefore, the performance of NPT should be strongly considered in these cases. There were no distinct clinical characteristics between LAR, AR, and non‐allergic rhinitis in children.

Full text

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wileyonlinelibrary.com/journal/pai Pediatr Allergy Immunol. 2019;30:296–304.
© 2019 EAACI and John Wiley and Sons A/S.
Published by John Wiley and Sons Ltd.
Received: 3 December 2018
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Revised: 9 January 2019
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Accepted: 10 January 2019
DOI : 10.1111/pa i.13 021
ORIGINAL ARTICLE
Airways Disease
Detection of local allergic rhinitis in children with chronic,
difficult‐to‐treat, non‐allergic rhinitis using multiple nasal
provocation tests
Olympia Tsilochristou1,2 | Marialena Kyriakakou2 | Ioanna Manolaraki2 |
John Lakoumentas2 | Ekaterini Tiligada3 | Pavlos Maragkoudakis4 |
Nikolaos Douladiris2 | Nikolaos G. Papadopoulos2,5
Abbreviations: AR, allergic rhinitis; IR , idiopathic rhinitis; LAR, local allergic rhinitis; M‐
NPT, mul tipl e nasal provo cation te st; NA R, non ‐alle rgic r hinit is; NHR , nasa l hype r‐reac tiv‐
ity; NP T, nasal p rovocation test; sIg E, serum aller gen‐specifi c IgE; SPT, skin pric k test.
1Peter Gorer Department of Immunobiology,
School of Immunology & Microbial
Sciences, King’s College London, London,
UK
2Allergy Department, 2nd Pediatric
Clinic, National and Kapodistrian University
of Athens, Athens, Greece
3Depar tment of Pharmacology, Medical
School, National and Kapodistrian University
of Athens, Athens, Greece
4Attikon University Hospital, National and
Kapodistrian University of Athens, Athens,
Greece
5Division of Infection, Immunit y &
Respiratory Medicine, University of
Manchester, Manchester, UK
Correspondence
Olympia Tsilochristou, Peter Gorer
Depar tment of Immunobiolog y, School of
Immunology & Microbial Sciences, King’s
College London, London, UK.
Email: Olympia.tsilochristou@kcl.ac.uk
Edited by: Ömer Kalaycı
Abstract
Background: There is little evidence on the incidence and characteristics of local al‐
lergic rhinitis (LAR) in children. Most studies have included subjects with perennial
rhinitis only, and results are based on the investigation of no more than three aller‐
gens per study. Our aim was to determine the proportion of children with LAR
amongst children with chronic, difficult‐to‐treat, perennial or seasonal, rhinitis but no
evidence of sensitization to aeroallergens, or other alternative diagnosis.
Methods: We performed multiple nasal provocation tests (M‐NPTs) with four locally
relevant aeroallergens (Phleum pratense, Olea europea, Alternaria alternata, and
Dermatophagoides pteronyssinus) in children with absence of aeroallergen sensitiza‐
tion, seen during a calendar year in a specialized rhinitis clinic. We additionally per‐
formed single NPT to children with allergic rhinitis (AR; positive control group). The
result of the NPT was based on symptoms and acoustic rhinometry. Identification of
nasal hyper‐reactivity (NHR) triggers was through a questionnaire.
Results: Local allergic rhinitis was confirmed in 29.2% (7/24) of the negative SPT/
blood testing population. All but one of the children reacted to one allergen and one
to two. All AR children had positive single NPT with results similar to the LAR. There
were no differences in age at examination and rhinitis onset, gender distribution,
family atopy, and past or current environment of residency, while the prevalence of
reported NHR triggers was comparable amongst the three groups.
Conclusion: This is the first pediatric study where the seasonal or perennial rhinitis
population was thoroughly tested for LAR against four aeroallergens. LAR is present
in a considerable proportion of children with chronic, difficult‐to‐treat rhinitis and no
sensitization to aeroallergens, and therefore, the performance of NPT should be
strongly considered in these cases. There were no distinct clinical characteristics be‐
tween LAR, AR, and non‐allergic rhinitis in children.

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1 | INTRODUCTION
Non‐infectious rhinitis is traditionally classified into allergic (AR)
and non‐allergic (NAR)1‐3 based on the clinical history and evidence
of systemic IgE production to relevant inhalant allergens. NAR is a
heterogeneous group of nasal conditions, some of which are associ‐
ated with a par ticular trigger or cause (eg, drug‐induced, hormonal),
although in the majority of patients with NAR, the cause is unknown
and the term idiopathic rhinitis (IR) has been used to categorize these
patients. Although NAR in adolescent/adult rhinitis populations is
common at ≥25%,4 its prevalence in childhood has not been well
established.4
Development of symptoms upon exposure to non‐specific trig‐
gers (temperature/humidity changes, strong odors/fragrances etc) is
known as nasal hyper‐reactivity (NHR)5 which is the key character‐
istic of patients with IR but a clinical feature of AR too.6 Given the
fact that the majority of the NAR and AR patients develop NHR ,7
the presence of NHR does not discriminate between NAR and AR .2
Nevertheless, in the era of precision medicine, grouping based on
distinct clinical patterns, known as phenotyping,2 is a priority. For
rhinitis (sub) phenotype characterization, various clinical criteria
can be used including age of onset, severity, symptom pattern/fre‐
quency, and triggers.
Another form of rhinitis, local allergic rhinitis (LAR), is a new
AR phenotype that has perplexed further the rhinitis classification.
Indeed, LAR is defined by a history of perennial or seasonal rhinitis
symptoms, the absence of systemic atopy (identified by skin prick
test [SPT] and/or serum allergen‐specific IgE [sIgE]) and a positive
specific nasal provocation test (NPT).8‐1 2 In a recent review,13 LAR
prevalence in 17 adult studies ranged from 7.4%14 to 69.6%
15 of
the NAR participants, with some of the studies having thoroughly
investigated patients for nasal reactivity to four common respira‐
tory allergens. Only a few pediatric LAR studies have been con‐
ducted16 ‐22; most of them have investigated children with perennial
symptoms only, while only three have had children challenged with
three aeroallergens each.18 ‐20 Similar to adults,13 the reported
prevalence ranged from 3.7%17 to 66.6%.19 Acknowledging these
gaps in knowledge, the aim of our study was to determine the
proportion of children with LAR amongst children with chronic,
difficult‐to‐treat, perennial or seasonal, rhinitis symptoms but no
evidence of sensitization to respiratory allergens, or other alterna‐
tive diagnosis, by performing NPTs to four common aeroallergens.
Our secondary objective was to elucidate whether LAR children
have any distinct clinical features including NHR triggers as op‐
posed to non‐LAR NAR children.
2 | METHODOLOGY
2.1 | Study population and design
The study population derived from the children seen within one cal‐
endar year (October 2016‐September 2017) in the joint allergy‐ENT
outpatient clinic of a tertiary pediatric hospital in Athens. This is an
outpatient clinic established to mainly address the needs of children
<18 years old with severe chronic rhinitis symptoms referred by
pediatricians, pediatric allergists, or ENT doctors.
The focus of our study was on children with negative skin and
blood sIgE testing who further fulfilled the following inclusion cri‐
teria: (a) age >6 years at examination, (b) rhinitis symptoms over the
last 12 months at least, and (c) absence of nasal anatomic abnor‐
malities that could justify the rhinitis symptoms. Eligible children
were prospectively recruited with the aim to undergo multiple NPT
(M‐NPT) to investigate the existence of LAR to common aeroal‐
lergens in Greece. During the outpatient clinic consultation, the
rhinitis symptoms as well as their duration, triggers and impact on
quality of life were recorded along with any other atopic comor‐
bidities (current and/or past) and family history of atopy. All chil‐
dren received an anterior rhinoscopy and SPT (house dust mites,
molds, grasses, weeds, trees, animal dander). Blood‐specific
IgEs (ImmunoCapPhadia, positive cutoff value at >0.35 kU/L) to
Dermatophagoides pteronyssinus, Alternaria alternata, Olea europea,
and Phleum pratense were obt ained, an d childre n we re booked to re‐
turn for an M‐NPT. All children with a positive M‐NPT were invited
for a confirmative single NPT to the eliciting allergen(s). For every
KEYWORDS
allergic rhinitis, LAR , local allergic rhinitis, multiple nasal provocation test, nasal hyper‐
reactivity, nasal provocation test, non‐allergic rhinitis, pediatric rhinitis, rhinitis, rhinitis
phenotypes
Key Message
Most local allergic rhinits (LAR) studies have taken place
with adults and only a few with children. Additionally, most
pediatric studies were on perennial rhinitis and in general,
have investigated no more than three allergens each. This
is the first published pediatric LAR study where partici‐
pants were thoroughly challenged against four (two sea‐
sonal and two perennial) common aeroallergens in
particular through the use of a standardized multiple nasal
provocation test protocol. Approximately one third of the
children were proven to be suffering with LAR which sup‐
ports the need for nasal provocation tests to be performed
in children with chronic non‐allergic rhintis.

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child wi th a positive M‐NP T, we additi onally per forme d a single NP T
to a main sensitizing allergen of a randomly picked AR child repre‐
senting the positive control group. Teenage patients and all carers
provided informed written consent. The study was approved by the
hospital Ethics Committee.
2.2 | NAR‐specific causes and NHR triggers
We additionally sought to identify triggers related to specific NAR
sub‐phenotypes (drug‐induced, hormonal, gustatory) that may be
relevant in childhood, through a doctor‐administered questionnaire.
We also addressed questions in relation to a number of non‐spe‐
cific environmental stimuli (cigarette smoke, temperature/humidity
changes, strong odors/fragrances, and other irritants) in order to in‐
vestigate for NHR.
2.3 | M‐NPT
Multiple nasal provocation tests were performed according to
the protocol developed by Rondon et al23 outside of the olive and
grass pollen season (typically May to July for Greece) and at days
th e pat ient s were asymp tom ati c (or with mi ld sym pto ms if patients
with perennial symptoms24). In short, four prevalent aeroallergens
were applied every 15 minutes with an established order depend‐
ing on the length of symptoms the children/carers reported, as
follows:
1. Perennial rhinitis: P. pr atens e, O. europea, A. alternata, and
D. pteronyssinus;
2. Seasonal rhinitis: A. alternata, D. pteronyssinus, O. europea, and
P. p ra tens e.
This order ensured that the most likely to be involved allergen(s)
was(were) tested last during the M‐NPT allowing the exclusion of as
many aeroallergens as possible before a positive re sponse would occur
in that visit. We decided to use the four allergens Rondon et al25 had
proposed as we had identified them as very common sensitizing aller‐
gens in children through the participation of our Allergy Department
in the Global Allergy and Asthma European Network (GA2LEN) Skin
Test Study. According to this study, in children seen previously in our
Allergy Department grasses and olive were the most common seasonal
outdoor sensitizing inhalant allergens at 49.5% and 35% sensitization
rates, respectively, while D pteronyssinus and Alternaria were the most
prevalent perennial allergens (of different genus) at 32.7% and 23.8%,
respectively.
The result of each NPT was assessed based on (a) subjective
(total of five—nasal obstruction, rhinorrhea, pruritus, sneezing,
and ocular symptoms—100 mm visual analogue scale [ VAS] scores)
and (b) objective parameters (nasal patency assessed by means of
acoustic rhinometry with the use of an A1 Acoustic Rhinometer;
GM Instruments LTD, Kilwinning, UK). For the latter, the parame‐
ter used was the volume of the nasal cavity from 2 to 5 cm (VOL
2‐5 cm), which is the volume of the nasal cavity suggested by the
Standardization Committee on Acoustic Rhinometry for the purpose
of estimating mucosal changes.26 Symptoms were recorded and
acoustic rhinometry was performed before the application of the
normal saline and henceforth 15 minutes from the administration of
the normal saline and each allergen. The test was considered posi‐
tive when there was an increase of ≥30% in the total VAS score to‐
gether with a decrease of ≥30% in VOL 2‐5 cm from at least one (the
most affected) nasal cavity. Both values were compared to the cor‐
responding post‐normal saline values. Children were given another
M‐NPT no earlier than 7 days from the positive M‐NPT23 while the
confirmative single NPT took place after at least 3 weeks.
Nasal provocation tests were unilateral with 0.07 mL (equiva‐
lent to one puff) of normal saline or the challenge solution (volume
recommended by the manufacturer [LETI]) sprayed through a nasal
dosing pump pointed toward the middle/inferior turbinate at 15‐
minute intervals. NPT details and exclusion criteria complied with
international guidelines.24 Fou r initially freeze‐dried and then recon‐
stituted allergen solutions of D pteronyssinus (100 HEP/mL), A alter-
nata (30 HEP/mL), O europea (30 HEP/mL), and P pratense (30 HEP/
mL) were used. Children were asked to remain for ≥1 hour after the
application of th e la st all erge n so that th ei r sympto ms could be mo n‐
itored. Families were requested to report back in case of symptoms
developing after leaving the allergy service.
2.4 | Data analysis
Quantitative variables (age, age of onset, and mean duration of
symptoms) were compared amongst groups using Wilcoxon’s
rank‐sum test (in case of two groups) or Kruskal‐Wallis test (in
case of three groups) due to lack of normality for the aforesaid
variables (as obtained by utilizing the Shapiro‐Wilk test for com‐
posite normality). Qualitative variables (all others) were compared
amongst groups using Pearson’s chi‐squared test of independ‐
ence. Statistical significance was taken when P < 0.05. Statistical
analysis was held with R, the language for statistical computing
(version 3.5.0, https://www.r‐project.org/contributors.html), with
the assistance of RStudio (version 1.1.383, DMCA, Boston, MA,
USA).
3 | RESULTS
Eighty‐six children were examined for the first time in the joint al‐
lergy‐ENT clinic within the defined time frame. Sixty‐two (72.1%)
had positive SPT with the majority (38.7%) found sensitized to
both perennial and seasonal allergens (35.5% to seasonal and
25.8% to perennial). Children with positive as opposed to those
with negative SPT had earlier onset of their rhinitis symptoms (at
5.9 ± 2.9 SD vs 7.5 ± 4.2 SD years, respectively) and were seen at
a younger age (9.4 ± 3.4 SD vs 10.6 ± 3.4 SD, respectively) with‐
out however these differences reaching statistical significance.
Gender distribution between these two groups did not differ
either.

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3.1 | Results from the M‐NPT and control AR NPT
All children with negative SPT (n = 24) fulfilled the inclusion criteria,
and upon receipt of their negative blood sIgE results were invited to
come back for an M‐NPT. None of the participants reacted to normal
saline. Seven children (29.2% of the negative SPT population/8.1%
of the whole study population; Figure 1) were diagnosed with LAR
based on positive M‐NPT with six of them reacting to a single aller‐
gen (two to A alternata, two to P pratense, one to O europea, and one
to D pteronyssinus) and one of them to two (D pteronyssinus and A.
alternata; Table 1). All reactions took place no later than 15 minutes
from the application of the eliciting allergen. More specifically, five
children reacted after the application of the 1st or the 2nd or the 3rd
allergen and returned back no earlier than 7 days for an M‐NPT to
three allergens (all but the eliciting) which in four cases were nega‐
tive (Table 1). Two children reacted after the application of the 4th
allergen receiving the diagnosis of LAR in one visit each (Table 1). In
all seven children, the mean reduction in VOL 2‐5 cm of one nostril
was 41.6% (9.6SD), which was accompanied by a 722% (555.3SD)
mean increase in the total VAS. Two out of the seven children ac‐
cepted to return for a confirmative single NPT to the allergen they
had reacted to (O europea, A alternata) and both had a positive out‐
come during their single NPT too (Table 1).
Furthermore, two out of the 24 children had >30% reduction in
VOL 2‐5 cm but presented/reported no accompanying symptoms,
and therefore, the outcome of their M‐NPT was determined as
negative and they were classified as non‐LAR NAR. There were no
reports that any of the 17 non‐LAR NAR subjects developed symp‐
toms (late phase reactions) after leaving the allergy ser vice.
Out of the 62 children with positive SPT, seven were randomly se‐
lected and undertook a single NPT to a major sensitizing allergen on the
ba sis of thei r SPT re s ults an d rel eva nt rh i niti s sy mpt oms. Th ey al l had po s‐
itive NPT defined by a 44.9% (14.2SD) mean decrease in VOL 2‐5 cm and
a 434% (243.4 SD) mean VAS increase (Table 1). VAS increase (P = 0.42)
and VOL 2‐5 cm decrease (P = 0.9) were comparable between the LAR
and AR control groups. On the contrar y, there was a statistically signif‐
icant decrease in VOL 2‐5 cm (P < 0.001) and VAS increase (P < 0.001)
when comparing the LAR, AR, and non‐LAR NAR NPT results.
Overall, there were no bronchial symptoms or in general symp‐
toms not involving the nose or the eyes taking place during any of the
NPT of the three groups. None of the families repor ted that a partici‐
pant experienced a late phase reaction after leaving the study center.
3.2 | Absence of remarkable nasal anatomic
abnormalities in the LAR, non‐LAR NAR, and
AR children
None of the children had signs of infectious rhinitis or significant
relevant nasal anatomic abnormality at the time of their recruitment,
while 3/7, 6/17, and 3/7 in the LAR, non‐L AR NAR, and AR group,
respectively, had no pathologic findings (data not shown). A mildly
inflamed mucosa was the most common finding in all groups.
3.3 | Clinical characteristics of LAR, non‐LAR
NAR, and AR children
Children with a positive M‐NPT were evaluated at a mean age of
11.4 years (3.6 SD) and had an onset of rhinitis symptoms at seven
(4.3 SD) years (Table 2). There were no differences in gender distri‐
bution, family atopy, past or current environment (urban or rural) of
residency either. Atopic dermatitis (71.4%) and asthma (41.2%) were
the most frequent current and/or past comorbidities in the LAR and
non‐LAR NAR subjects, respectively, as opposed to conjunctivitis
(42.9%) in the AR group. Notably, atopic dermatitis appeared to be
a particularly common comorbidity in LAR when compared to the
other two groups (P = 0.06).
FIGURE 1 Precise diagnosis of rhinitis phenotypes based on multiple nasal provocation test (M‐NPT). Left figure shows the diagnosis the
study population (n = 86) received based on their skin prick test (SPT) and sIgE results. Right figure shows the diagnosis the study population
received following M‐NPT in addition to SPT/sIgE results. AR, allergic rhinitis; LAR, local allergic rhinitis; NAR, non‐allergic rhinitis [Colour
figure can be viewed at wileyonlinelibrary.com]

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TABLE 1 Objective and subjective parameter results of all study nasal provocations tests and related clinical details
Patient VOL 0‐5 cm (%) VOL 2‐5 cm (%) VOL 0‐3 cm (%) VAS (%)
Positive af ter
application of
Duration of symptoms
during the last 12 mo
Specific months symptoms
occurred the last 12 mo
Number of M‐NPT
visits needed
Positive M‐NPT (LAR, N = 7)
126 30 22 350 Alternaria alternata 2August‐September 2
251 56 45 1600 Dermatophagoides
pteronyssinus
10 August‐June 1
341 46 28 500 Phleum pratense 3February‐April 1
439 44 28 138 P pretense 6March‐May & September‐October 2
541 45 37 800 Olea europea 2April‐May 2
629 30 32 228 A alternate 12 All year 2
7a 43 49 28 1500 A alternata 10 September‐June 2
7b 29 33 30 660 D pteronyssinus
Mean (SD) 37.4 (8.6) 41.6 (9.6) 31.3 (6.98) 722
(555.3)
6.4 (4.2)
Confirmative single NPT of positive M‐NPT
540 47 32 850 O europea 2April‐May N/A
635 35 37 400 A alternata 12 All year N/A
Mean (SD) 37.5 (3.5) 41 (8.5) 34.5 (3.5) 625
(318.2)
AR single NPT (N = 7)
842 45 29 500 D pteronyssinus 11 January‐July & September‐October N/A
926 30 19 600 P pratense 5April‐June & September‐October N/A
10 51 56 45 850 D pteronyssinus 5April‐June & September‐October N /A
11 27 31 20 200 O europea 4March‐June N /A
12 63 70 50 400 A alternata 5March‐June & October N/A
13 39 44 28 138 D pteronyssinus 4November‐February N/A
14 24 38 12 350 P pratense 9September‐May N/A
Mean (SD) 38.9 (14.5) 44.9(14.2) 29 (14) 434
(243.4)
6.1 (2.7)
Negative M‐NPT (non‐LAR NAR, N = 17)
Mean (SD) 3.4 (13.2) 3.4 (16.3) 2.7 (12) 0.28
(0.37)
N/A 6.2 (2.4) N/A 1 (0)
Table presents the decrease in volume (VOL) 0‐5, 2‐5, and 0‐3 cm of one nostril and the corresponding accompanying increase in the total visual analogue scales (VAS) as well as the eliciting allergen, dura‐
tion, and seasonality of symptoms in the (a) seven children that had positive multiple nasal provocation tests (M‐NPT) (diagnosed with local allergic rhinitis [LAR]); one child had two positive provocation
test s (7a & 7b), (b) seven allergic rhinitis (AR) children (positive control group) that all had positive NPT, and (c) 17 children that had negative M‐NPT (only mean [SD] values shown). A nasal provocation test
was considered positive when there was an increase of 30% or greater in the total VAS score together with a decrease of 30% or greater in VOL 2‐5 cm from at least one nasal cavity (the most affected);
both values were compared to the corresponding post‐normal saline values.

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In all groups, the majority of children had persistent moderate/
severe rhinitis according to the ARIA classification1 and reported
symptoms of similar duration over the last calendar year (Table 3).
Nasal blockage was the main nasal symptom in 71.4%, 58.8%, and
57.1% of the LAR, non‐LAR NAR, and AR children, respectively, with
the majority of carers mentioning the children were sleeping with
their mouth open. Postnasal drip was not infrequent (28.6% in LAR,
41.2% in non‐LAR NAR, and 28.6% in AR), while hyposmia was ab‐
sent in the L AR group only.
3.4 | Specific and non‐specific triggers of rhinitis
symptoms in LAR, non‐LAR NAR, and AR children
Overall, the prevalence of reported specific causes or non‐specific‐
NHR triggers in the three groups was comparable (Table S1).
No children had known hormonal disorder or rhinitis reactions
following aspirin/NSAIDs or any other medication use. One child
from each group had rhinitis symptoms related to prolonged nasal
decongestant use, while two in the LAR and one in the non‐LAR
NAR had symptoms upon spicy food consumption.
With regard to non‐specific NHR triggers, there were propor‐
tionately more children in the L AR (n = 6/7, 85.7%) as well as the AR
(n = 5/7, 71.4%) vs the non‐LAR NAR group (n = 8/17, 47.1%) react‐
ing to at least one trigger (P = 0.17).
4 | DISCUSSION
Although Huggins and Brostoff first detected sIgE to D pteronyssinus
in the nasal secretions of individuals with negative SPT results and
AR (N = 7) LAR (N = 7) non‐L AR NAR (N = 17) P‐value
Demographics
Age (y) at examination
Mean (SD) 12.4 (3.2) 11.4 (3.6) 10.3 (3.4) 0.43a
Range 7‐17 7‐16 6 ‐16
Median 12 11 10
Age (y) at rhinitis onset
Mean (SD) 8 (4.3) 7 (4.3) 7.7 (4.3) 0.91a
Range 2‐14 2‐14 1‐1 4
Median 75.5 7. 5
Gender
Male, n (%) 5 (71.4) 4 (57.1) 8 (47.1) 0.55b
Brought up in urban
Yes, n (%) 7 (100) 6 (85.7) 17 (100) 0.17b
Current residency in urban
Yes, n (%) 7 (100) 6 (85.7) 17 (100) 0.17b
Atopy of close family member
Yes, n (%) 2 (28.6) 4 (57.1) 6 (35.3) 0.50b
Comorbidities
Conjunctivitis
Yes, n (%) 3 (42.9) 2 (28.6) 3 (17.6) 0.43b
Asthma symptoms
Yes, n (%) 1 (14.3) 3 (42.9) 7 (41.2) 0.41b
Atopic dermatitis
Yes, n (%) 1 (14.3) 5 (71.4) 5 (29.4) 0.06b
Food allergy
Yes, n (%) 0 (0) 1 (14.3) 1 (5.9) 0.55b
Table presents data on demographics and comorbidities of seven randomly selected children with
allergic rhinitis (AR) and of all children with negative skin prick test results (n = 24). Data of the latter
are divided into those diagnosed with local allergic rhinitis (LAR) vs those diagnosed with non‐local
non‐allergic rhinitis (non‐LAR NAR) following a multiple specific nasal allergen challenge with four
common inhalant allergens in Greece.
P‐values were extracted using
aKruskal‐Wallis test.
bPearson’s chi‐squared test of independence.
TABLE 2 Demographics and
Comorbidities of children diagnosed with
AR, LAR, or non‐LAR NAR

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absence of serum sIgE in 1975,27 L AR is still not widely accepted as
an entity and reports on its prevalence vary. Most LAR studies have
taken place with adults and only a few with children. Additionally,
most pediatric studies were on perennial rhinitis and, in general,
have investigated no more than three allergens each, while the re‐
sults are highly variable. Furthermore, there is limited information
on whether LAR patients have distinct clinical features that could
potentially support the clinician to suspect the existence of L AR as
opposed to NAR.
In this study, we demonstrated the presence of LAR in almost
one third (29.2%, n = 7/24) of our population that included children
with chronic, problematic, seasonal or perennial, rhinitis, negative
allergy investigations for numerous respirator y allergens, and ab‐
sence of relevant nasal anatomic abnormalities. This LAR propor‐
tion is comparable to the 25% reported by the only pediatric study18
that investigated children with seasonal or perennial rhinitis (NPT
performed with D pteronyssinus, D. farinae, grass mix). Meanwhile,
LAR prevalence in studies with children with perennial symptoms
ranged from 3.7%17 to 66.6%19 vs 44.4%21 to 60.3%20 reported in
children with seasonal symptoms. In our study, 6/7 LAR children
were monosensitized and one was co‐sensitized to the two peren‐
nial allergens checked. Of the three pediatric studies that did NPT to
more than one aeroallergen, Duman et al18 reported just monosen‐
sitized (n = 7), Zicari et al19 one dual‐sensitized (one out of 12 LAR)
in contrast to Krajewska et al20 who reported that nearly 40% of the
seasonal LAR children were dual‐sensitized (21 out of 53 LAR).
We did not identify any particular clinical characteristics of the
LAR children; there were no differences in terms of gender distribu‐
ti on, age of rhi n itis onset , rhi niti s durat ion, se ver ity or impac t on qu al‐
ity of life (Tables 2 and 3), which enhances what has bee n reported in
the literature.18,21,22 Nasal blockage was the predominant symptom
in all groups with the majority of children reported to be sleeping
AR (N = 7) LAR (N = 7)
non‐LAR NAR
(N = 17) P‐value
Symptom duration (mo) the last 12 mo
Mean (SD) 6.1 (2.7) 6.4 (4.2) 6.2 (2.4) 0.99a
Range 4‐11 2‐12 3‐12
Median 5 6 6
ARIA classification
Intermittent mild, n (%) 0 (0) 0 (0) 0 (0) 1b
Intermittent moderate/
severe, n (%)
1 (14.3) 0 (0) 2 (11.8)
Persistent mild, n (%) 0 (0) 1 (14.3) 1 (5.9)
Persistent moderate/severe,
n (%)
6 (85.7) 6 (85.7) 14 (82.4)
Main nasal symptom
Blockage, n (%) 4 (57.1) 5 (71.4) 10 (58.8) 0.51b
Blockage & rhinorrhea, n (%) 2 (28.6) 2 (28.6) 3 (17.6)
Rhinorrhea, n (%) 0 (0) 0 (0) 3 (17.6)
Pruritus, n (%) 0 (0) 0 (0) 1 (5.9)
Sneezing, n (%) 1 (14.3) 0 (0) 0 (0)
Postnasal drip
Yes, n (%) 2 (28.6) 2 (28.6) 7 (41.2) 0.77b
Sleep with open mouth
Yes, n (%) 4 (57.1) 6 (85.7) 15 (88.2) 0.20b
Snoring
Yes, n (%) 3 (42.9) 2 (28.6) 10 (58.8) 0.38b
Hyposmia
Yes, n (%) 4 (57.1) 0 (0) 7 (41.2) 0.06b
Table presents details on rhinitis‐related symptoms of seven randomly selected children with allergic
rhinitis (AR) and of all children with negative skin prick test results (N = 24). Data of the latter are
divided into those diagnosed with local allergic rhinitis (LAR) vs those diagnosed with non‐local
non‐alle rgic rh in itis (non‐L AR NAR) fol lowing a mu lt iple sp ecifi c nasal all ergen cha llenge wit h 4 com‐
mon inhalant allergens in Greece.
P‐values were extracted using
aKruskal‐Wallis test.
bPearson’s chi‐squared test of independence.
TABLE 3 Rhinitis‐related symptoms of
children diagnosed with AR, LAR or
non‐LAR NAR

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TSILOCHR ISTOU e T aL.
with an open mouth. We found that atopic dermatitis was the most
common (71.4%) comorbidity in the LAR children as opposed to con‐
junctivitis (95%) reported by Blanca et al.21 On the contrary, asthma
was most common (41.2%) in our non‐LAR NAR children in agree‐
ment with Blanca et al. Notably, atopic dermatitis, considered as the
start of the atopic march, was a particularly common comorbidity
in the LAR children when compared to the other two groups which
supports the notion that L AR may be a precursor of AR.
We additionally looked for the presence of NAR‐specific causes
and NHR non‐specific triggers through the history of symptoms
and reported comparable prevalence of these between the groups
(Table S1). Interestingly though, a higher proportion of children in
the LAR (85.7%) group reported symptoms to at least one non‐spe‐
cific NHR trigger as opposed to the AR (71.4%) and non‐L AR NAR
(47.1%) group without this being statistically significant. It has been
already reported that NHR cannot discriminate between NAR and
AR,7 and our results extend this observation in LAR. These results
indicate that it may be difficult for a clinician to distinguish the LAR
children based on the clinical history alone. This supports the need
for NPT, preferably to more than one aeroallergens, to be performed
in children with chronic rhinitis and no evidence of sensitization to
inhalant allergens.
There are some limitations to our study, mostly related to the
relatively small number of patients included, which may explain the
lack of statistically significant differences between the groups. The
study population derived from a clinic meant to evaluate children
with uncontrolled rhinitis and LAR proportion may have been differ‐
ent if more children with mild intermittent rhinitis were involved. We
did not perform non‐specific NPT (eg, dry cold air) to verify NHR.
Although we checked participants against four common aeroaller‐
gens in Greece, we cannot exclude that there may be other relevant
aeroallergens involved in LAR. Lastly, we did not investigate for local
production of allergy inflammatory mediators or sIgE.
To the best of our knowledge, this is the first published pe‐
diatric LAR study where participants were thoroughly challenged
against four (two seasonal and two perennial) common aeroaller‐
gens in part icular thr ou gh the use of the standardized M‐NPT pro‐
tocol,23 while we addressed the presence of NHR as an additional
way to potentially set a differential diagnosis. Study strengths
also include rhinitis comprehensive evaluation; SPT to numerous
inhalant allergens and not just the four checked at M‐NPT and
anterior rhinoscopy to exclude the presence of significant nasal
anatomic abnormalities that could justify the rhinitis symptoms.
Addit ionally, we included a positive control gro up (AR) whose NPT
results were comparable to the positive M‐NPT and used strict
NPT positivity criteria comprising of both subjective and object ive
criteria.
In conclusion, in this study we demonstrated that approximately
one third of the children that would have been given the diagnosis of
NAR were proven to be suffering with LAR (Figure 1). Therefore, LAR
seems to affect a considerable proportion of this population (children
with chronic, problematic, seasonal or perennial, rhinitis) and the per‐
formance of NPT should be strongly considered pending that there is
trained staff to execute them. In the era of precision medicine, it is
possible that children diagnosed with LAR may benefit from allergen
immunotherapy that needs to be further evaluated.
ACKNOWLEDGMENTS
We thank the nurses, doctors, and administrative staff of the Allergy
Department at the 2nd Pediatric Clinic (National and Kapodistrian
University of Athens, Athens, Greece) for clinical and logistic assis‐
tance over the period of the study and also Dr Aikaterini Lala of the
ENT Department, “P & A. Kuriakou” Children’s Hospital, Athens, for
performing the nasal examination. Above all, we are indebted to all
of the children and their families who generously took part in this
stud y.
CONFLICT OF INTEREST
The authors declare no conflict of interest relevant to the submitted
work.
AUTHOR CONTRIBUTION
OT conceived and designed the study, performed nasal provoca‐
tion tests, selected and interpreted the study data, and drafted
the manuscript; MK and IM performed nasal provocations tests; JL
performed the statistical analysis of the data; ET, PM, and ND pro‐
vid ed input in the conception and design of the study protocol; NGP
conceived and designed the study, interpreted the study data, and
reviewed intermediate drafts of the manuscript. All authors have
critically revised the manuscript and have given final approval of the
version submitted.
ORCID
Olympia Tsilochristou https://orcid.org/0000‐0002‐4540‐4602
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SUPPORTING INFORMATION
Additional supporting information may be found online in the
Supporting Information section at the end of the article.
How to cite this article: Tsilochristou O, Kyriakakou M,
Manolaraki I, et al. Detection of local allergic rhinitis in children
with chronic, difficult‐to‐treat, non‐allergic rhinitis using
multiple nasal provocation tests. Pediatr Allergy Immunol.
2019;30:296–304. htt ps://doi.org/10.1111/pai.13 021