ORIGINAL ARTICLE
Prognostic value of nasal cytology and clinical factors in nasal polyps
development in patients at risk: can the beginning predict the end?
Eugenio De Corso, MD, PhD1 , Daniela Lucidi, MD1 , Mariapina Battista, MD1 , Matteo Romanello, MD1 ,
Carla De Vita, MD1 , Silvia Baroni, MD2 , Chiara Autilio, MS2 , Jacopo Galli, Prof1 and Gaetano Paludetti, Prof1
Background: We evaluated the prognostic value of nasal
cytology and clinical factors in predicting nasal polyp (NP)
development in patients with history of nonallergic chronic
sinonasal inammation.
Methods: This was a retrospective case-control study of
295 patients followed at our institution for a mean of
85.70 19.41 months. According to the inclusion criteria
we enrolled 84 cases with persistent eosinophilic nonal-
lergic sinonasal inammation (group A) and 106 cases with
neutrophilic inammation (group B), both without evidence
of NPs at the baseline. We considered as controls 105
patients aected by nonallergic noninfectious vasomotor
rhinitis without evidence of inammation at nasal cytology
(group C). Patients were checked every 6 months for NPs.
Temporal analyses was performed by Kaplan-Mayer curves
and odds ratios were evaluated by logistic regression
analyses.
Results: The percentage of patients that developed NPs
was higher in group A (29/84 [34.52%]) than in group B
(17/106 [16.03%]) and group C (5/104 [4.7%]) (p < 0.05).
Logistic regression analyses showed that eosinophilic pa-
tients had a higher risk of NP development over the years
C hronic rhinosinusitis with nasal polyps (CRSwNP)
represents a broad spectrum of different phenotypes
and endotypes. Phenotypes can be defined by differences in
clinical aspects, such as severity, recurrence, conventional
therapy response, and association with comorbidities, and
1 Department of Head and Neck Surgery, Institute of
Otorhinolaryngology, Catholic University School of Medicine and
Surgery, Rome, Italy; 2 Department of Diagnostic and Laboratory
Medicine, Institute of Biochemistry and Clinical Biochemistry, Catholic
University School of Medicine and Surgery, Rome, Italy
Correspondence to: Eugenio De Corso, MD, PhD, A. Gemelli Hospital
Foundation, Catholic University of the Sacred Heart, Head and Neck
Surgery Area, Institute of Otorhinolaryngology, Largo A. Gemelli n.1, 00168,
Rome, Italy; e-mail address: eugenio.decorso@policlinicogemelli.it
Potential conflict of interest: None provided.
Received: 23 November 2016; Revised: 12 May 2017; Accepted: 30 May 2017
DOI: 10.1002/alr.21979
View this article online at wileyonlinelibrary.com.
861 International Forum of Allergy & Rhinology, Vol. 7, No. 9, September 2017
than neutrophilic patients compared to controls (odds
ratio [OR], 10.55 vs 3.2). We also demonstrated that hyper-
eosinophilia, asthma, and aspirin intolerance may increase
the OR dierently in eosinophilic patients.
Conclusion: Our data suggest that early identication of
inammatory paerns and associated clinical factors in
patients aected by chronic nonallergic sinonasal inam-
mation have a prognostic value that can help to identify
patients with dierent risks of NP development. Our data
conrm that detection of nasal eosinophilic inammation
represents an early marker for identication of a more ag-
gressive inammatory phenotype.  C 2017 ARS-AAOA, LLC.
Key Words:
eosinophil; allergy; chronic rhinosinusitis with nasal polyps;
nonallergic rhinitis; asthma
How to Cite this Article:
De Corso E, Lucidi D, Baista M, et al. Prognostic value
of nasal cytology and clinical factors in nasal polyps devel-
opment in patients at risk: can the beginning predict the
end? Int Forum Allergy Rhinol. 2017;7:861867.
have a negative impact on the quality of life. Endotypes
can be defined by differences in pathogenetic mechanisms
and association with different inflammatory patterns and
corresponding biomarkers.1, 2
Several authors have tried to distinguish nasal polyp
(NP) patients based on predominant inflammatory cell
type/cytokine expression; the most common classification
differentiates them into eosinophilic CRSwNP and non-
eosinophilic CRSwNP.35 In Western countries, CRSwNP
is mostly characterized by eosinophilic inflammation with
a prevalence ranging between 70% and 90% accord-
ing to different reports.6 In Asian countries CRSwNP is
mainly non-eosinophilic,7, 8 even though the prevalence
of eosinophilic pattern seems to have increased recently.9
From a cytological point of view, nasal eosinophilic inflam-
mation represents the most significant predictive factor of a
more aggressive phenotype characterized by a higher polyp
recurrence rate after surgery.10, 11
De Corso et al.
TABLE 1. Epidemiologic data and comorbidities
Median age years (range) Sexa
Group A 41 (1870) M: 33 (39.3); F: 51 (60.7)
Group B 42 (1969) M: 49 (46.2); F: 57 (53.8)
Group C 43 (2070) M: 52 (49.5); F: 53 (50.5)
a
Values are n (%).
AERD = aspirin-exacerbated respiratory disease; F = female; M = male.
In a previous study,12 we underlined the importance
of defining the cellular inflammatory pattern in patients
with nonallergic chronic sinonasal inflammation in terms
of severity of symptoms and risk of comorbidities. Never-
theless, in these patients no standardized prognostic algo-
rithm is available to define the risk of NP development over
the years. The aim of our study was to assess the predictive
value of nasal cytology and associated clinical factors in
patients affected by chronic nonallergic sinonasal inflam-
mation in terms of NP development over a 10-year period.
Patients and methods
Study design
This is a retrospective case-control study of 295 patients
firstly referring to our institution (A. Gemelli Hospital
Foundation, Catholic University of Sacred Heart, Rome,
Italy) and followed between January 2006 and December
2016. Patients were followed for a mean period of 84.70
19.41 months (range, 60 to 120 months) with regular
6-month visits.
Study population and inclusion criteria
Cases enrolled at baseline were selected based on the fol-
lowing inclusion criteria: clinical symptoms of nonallergic
noninfectious persistent rhinitis, selective eosinophilic, or
neutrophilic inflammation in the sinonasal mucosa detected
by nasal cytology for more than 12 weeks; no previous
sinonasal surgery; nonallergic status; no evidence of NPs at
nasal endoscopy (Meltzer endoscopic score = 0)13 ; and no
evidence of CRS at computed tomography (CT) scan (bi-
lateral Lund-Mackay score: 0).14 The cutoff of eosinophilic
and neutrophilic infiltration was established based on lit-
erature data12, 15 ; namely, eosinophils accounting for over
20% and neutrophils for over 50% of total cellularity and
without any evidence of infection.
Based on the inclusion criteria we identified 92
eosinophilic nonallergic patients (84 patients adher-
ent to the follow-up [group A] and included; 8 patients
lost to follow-up) and 119 neutrophilic nonallergic pa-
tients (106 patients [group B] adherent to follow up; 13
were missed at follow-up). Finally, as a control group we
identified 117 patients affected by nonallergic nonin-
fectious vasomotor rhinitis responding to the following
criteria: clinical symptoms of nonallergic noninfectious
Family historya Hypereosinophiliaa AERDa Asthma Coexisting asthma AERDa
18/84 (21.42) 27/84 (32.14) 9/84 (10.7) 12/84 (14.2) 5/84 (5.9)
20/106 (18.86) 0/106 (0) 0/106 (0) 6/106 (5.6) 0/106 (0)
25/105 (23.8) 0/105 (0) 0/105 (0) 4/105 (3.8) 0/105 (0)
persistent rhinitis; no detectable inflammation at nasal cy-
tology (ie, absence of inflammatory cells at nasal cytology
at least twice in 12 weeks); nonallergic status; no evidence
of NPs and nasal discharge at nasal endoscopy (Meltzer
endoscopic score = 0); and no evidence of CRS at CT scan
(bilateral Lund-Mackay score: 0). We included in the study
105 adherent patients (group C) whereas 12 were lost to
follow-up.
Epidemiological data and comorbidities are shown in
Table 1. Asthma and aspirin-exacerbated respiratory dis-
ease (AERD) were defined according to Allergic Rhinitis
and its Impact on Asthma Guidelines (ARIA).16 Hypere-
osinophilia was defined as a peripheral blood eosinophil
percentage count greater than 6% with a corresponding
absolute eosinophil count greater than 600/mm317 .
Follow-up data collection
Patients were evaluated by 2 experienced rhinologists at
baseline and then every 6 months. All patients and controls
were treated chronically with saline irrigation and topical
corticosteroids administered daily by nasal spray (mometa-
sone furoate 200 g twice per day for 2 weeks per month).
During the 6-month checkup, patients underwent clinical
reevaluation, sinonasal endoscopy, nasal cytology, allergy
retesting, and pulmonary function evaluation.
Definition of CRSwNP was assumed according to the
European Position Paper on Rhinosinusitis and Nasal
Polyps (EPOS) criteria6 and American clinical practice
guidelines.18 The main end point of follow-up was NP iden-
tification that was achieved for a Meltzer endoscopic grad-
ing greater than 0. Patients developing NPs were dropped
from the study and were not considered in statistical anal-
yses. In patients developing NPs local and/or oral corti-
costeroids were used as first-line therapy and functional
endoscopic sinus surgery (FESS) was considered in case of
unsatisfying control of symptoms.
Nasal cytology
Nasal cytology was performed according to a previous
report.15 Samples of mucosa were obtained by scraping
the medium third of the inferior turbinate bilaterally with
a rhinoprobe (Farmark s.n.c., Milan, Italy). Samples were
delicately spread on glass slides, immediately fixed in 95%
ethanol, and stained with May-Grunwald-Giemsa (Carlo
Erba, Milan, Italy). Cell counts were performed on scraped
International Forum of Allergy & Rhinology, Vol. 7, No. 9, September 2017 862
Predictive value of nasal cytology in NP onset

TABLE 2. Stratification of patients according to comorbidities and NP development during follow-up*

Group A Group B Group C

NP NP free p NP NP free NP NP free p

Hypereosinophilia 10/29 (34.5%) 17/55 (30.9%) ns 0/17 (0%) 0/89 (0%) ns 0/5 (0%) 0/100 (0%) ns
AERD 6/29 (20.7%)a 3/55 (5.4%)a <0.05 0/17 (0%) 0/89 (0%) ns 0/5 (0%) 0/100 (0%) ns
Asthma 9/29 (31%) b
3/55 (5.4%) b
<0.05 1/17 (5.8%) 5/89 (5.6%) ns 1/5 (20%) 4/100 (4%) ns
Coexisting asthma and AERD 3/29 (10.3%) c
1/55 (1.8%) c
<0.05 0/17 (0%) 0/89 (0%) ns 0/5 (0%) 0/100 (0%) ns

*Differences were compared by Pearsons chi square test (p < 0.05).

a
Difference was statistically significant with a p < 0,05. ________________________________________.
b
Difference was statistically significant with a p < 0,05. ________________________________________.
c
Difference was statistically significant with a p < 0,05. ________________________________________.
AERD = aspirin-exacerbated respiratory disease; NP = nasal polyp; ns = not significant.

nasal tissue by microscopic examination (Nikon E600;
Nikon, Milan, Italy). The cell count was performed on
10 fields at 1000 magnification under immersion. Lo-
cal eosinophilic infiltration was measured as the percent-
age of eosinophils observed among the polymorphonuclear
and mononuclear cells (epithelial cells excluded), and was
reported as an average of 10 fields examined at high mag-
nification (1000). An experienced cytologist (E.D.C) who
was unaware of the clinical status of patients blindly exam-
ined samples.
Statistical analysis
Statistical analysis was performed using the SPSS package
(IBM SPSS Statistics for Macintosh, Version 22.0, Armonk,
NY: IBM Corp.). Comparisons between groups were per-
formed using Mann-Whitney U and chi square tests. The
5-year and 10-year polyp-free cumulative probability from
baseline were estimated by the Kaplan-Meier function. Dif-
ferences between Kaplan-Meier estimates were compared
by log-rank test and statistical significance was set for a p
value lower than 0.05.
Estimation of risk was obtained by logistic regression
analyses. We performed univariate analyses to estimate the
risk of developing NPs for persistent nasal eosinophilia pa-
tients and persistent nasal neutrophilia patients vs controls.
A multinomial logistic regression analyses was possible only
for eosinophilic patient to define clinical factors influencing
the risk. The results were considered significant at a p value
<0.05.
Results
Percentage of NP development
Analysis of follow-up outcomes revealed that the per-
centage of patients who developed NPs was higher in
group A than in groups B and C. Namely, in group A,
29 of 84 patients (34.5%) developed bilateral sinonasal
polyposis after a median time of 40 months. In group B, 17
of 106 patients (16%) developed bilateral nasal polyposis
after a median time of 43 months. Finally, in the control
group we never observed bilateral NPs, although 5 of 105
(4.7%) patients developed unilateral NPs after a median
of 40 months (2 cases of antrochoanal polyps and 3 of
unilateral involvement due to odontogenic etiology). The
intergroup comparison showed that the differences among
percentages was statistically significant (p < 0.05). Analy-
sis of comorbidities in group A revealed that NP develop-
ment was significantly higher in asthmatic and/or AERD
patients than in negative ones, as shown in Table 2. In
group A, 9 of 84 patients were AERD, 5 of which in asso-
ciation with asthma. These subjects developed NPs during
follow-up, and for this reason in these patients we assumed
that chronic eosinophilic inflammation could represent a
forerunner of Samters syndrome.
Temporal analyses of NP onset
To evaluate differences in the temporal onset of NPs in
the 3 groups, we performed statistical analysis with the
Kaplan-Meier function, as shown in Figure 1. The log rank
test demonstrated that differences between curves was sta-
tistically significant (p < 0.05). The 5-year and 10-year cu-
mulative probabilities of remaining polyp-free for groups
A, B, and C, were respectively 0.74 and 0.64 in group A,
0.90 and 0.84 in group B, and 0.95 and 0.95 in the control
group.
Estimating the risk of development of NPs
Univariate logistic regression analysis showed that patients
in group A had a risk of developing NPs that was 10.55
times higher than controls (odds ratio [OR] 10.55; 95%
confidence interval [CI], 3.89 to 8.28; p < 0.025) and 2.76
times higher than patients in group B (OR 2.76; 95% CI,
1.39 to 5.48; p < 0.025). Patients in group B had a risk of
developing polyps that was 3.82 times higher than controls
(OR 3.82; 95% CI, 1.35 to 10.78; p < 0.025) (Table 3).
Factors associated with the development
of CRSwNP in eosinophilic patients
Multinomial logistic regression analysis was possible only
for eosinophilic patients (group A). All factors analyzed
are reported in Table 3 (we counted not only baseline

863 International Forum of Allergy & Rhinology, Vol. 7, No. 9, September 2017
De Corso et al.
FIGURE 1. Cumulative probabilities of remaining free of polyps over 10 years of follow-up.
comorbidities but also those with onset during follow-up).
Several comorbidities might increase the risk of NP devel-
opment. Namely, asthmatic patients had a risk that was
3.09 (95% CI, 1.06 to 9.03; p < 0.05) times higher com-
pared to nonasthmatic ones; AERD patients had an OR of
4.6 (95% CI, 1.8 to 15.28; p < 0.05) compared to non-
intolerant patients; asthma and AERD patients had a OR
of 6.62 vs non-AERD and nonasthmatic patients (95% CI,
1.17 to 37.41; p < 0.025).
Allergy retesting in group A during follow-up showed
sensitization to inhalant allergens in 10 patients, 4 of whom
developed sinonasal polyps. The prevalence of NP onset in
sensitized patients vs negative ones was 4 of 10 (40%) vs
19 of 74 (25.67%), but the difference was not statistically
significant. Furthermore, the prevalence of NP onset in mast
cell-positive patients at nasal cytology vs negative ones was
6/16 (37%) vs 23/68 (29.5%); the difference did not reach
statistical significance (p > 0.05).
Management of patients that develop NPs
In patients developing NPs, we applied a therapeu-
tic approach based on EPOS guidelines.19 In group A,
29 patients who developed NPs symptoms were con-
trolled by local and/or oral corticosteroids in 16 of
29(55.2%), whereas FESS was required in 13 of 29
(44.8%). In group B, 17 patients developed NPs; symp-
toms were controlled by local and/or oral corticosteroid
in 7 of 17 patients (41.2%), whereas 10 of 17 patients
International Forum of Allergy & Rhinology, Vol. 7, No. 9, September 2017
(58.8%) needed FESS. All 5 control patients underwent
surgery.
Discussion
In the last few decades there has been increased interest
about the clinical aspects of CRSwNP, whereas there is
still discussion about determination of different endotypes
and corresponding phenotypes. Different endotypes may be
associated with different inflammatory pattern and some
authors19, 20 have suggested that they may have a different
prognostic value.
Patients with tissue eosinophilia (eosinophilic NPs), com-
pared to non-eosinophilic patients, are more frequently af-
fected by extensive bilateral sinus disease (ie, higher CT and
endoscopy scores), and have higher postoperative symp-
tom scores, less improvement in both disease-specific and
general quality of life, higher polyp recurrence rate, and
higher prevalence of bronchial asthma and AERD. For all
these reason eosinophilic CRSwNP represents a challeng-
ing clinical entity with a particular disease severity and even
though it has marked clinical response to administration of
steroid therapy there is a strong tendency for recurrence
after surgery.10, 19
Patients with neutrophils (non-eosinophilic NPs), on the
other hand, showed a better response to endoscopic sinus
surgery (ESS) and to macrolide therapy (long-term low-dose
administration) than eosinophilic patients. Hyposmia is not
864
Predictive value of nasal cytology in NP onset

TABLE 3. Logistic regression analyses results estimating the risk of nasal polyp development

Patients characteristic Odds ratio 95% confidence interval Significance

Univariate logistic regression analyses

Persistent nasal eosinophilia vs controls 10.55 3.6628.8 p < 0.001
Persistent nasal eosinophilia vs persistent nasal neutrophilia 2.76 1.395.48 p = 0.007
Persistent nasal neutrophilia vs controls 3.82 1.3510.37 p = 0.003
Multinomial logistic regression analyses
Persistent nasal eosinophilia with familiar history vs persistent nasal eosinophilia without 0.43 0.141.31 p = 0.13
familiar history
Persistent nasal eosinophilia with increased eosinophil blood count vs persistent nasal 1.18 0.453.06 p = 0.73
eosinophilia without one
Persistent nasal eosinophilia and presence of mast cells in nasal cytology vs persistent 0.72 0.232.21 p = 0.52
nasal eosinophilia without mast cells in nasal cytology
Persistent nasal eosinophilia and asthma vs persistent nasal eosinophilia without asthma 3.09 1.069.03 p = 0.02
Persistent nasal eosinophilia with AERD vs persistent nasal eosinophilia without AERD 4.6 1.815.28 p = 0.02
Persistent nasal eosinophilia with asthma and AERD vs persistent nasal eosinophilia 6.62 1.1737.41 p = 0.01
without AERD and without asthma
AERD = aspirin-exacerbated respiratory disease.

a common symptom among neutrophilic patients and
they present prevalent maxillary sinus involvement accord-
ing to the evidence that the middle meatus or ostiomeatal
complex (OMC) may have a fundamental role in the patho-
genesis of non-eosinophilic NPs.2124
Non-eosinophilic CRSwNP is considered by some
authors25, 26 as extrinsic rhinosinusitis, to originate from
external stimuli, such as bacteria and allergens. Intrinsic
mechanisms of the nasal mucosa are now in the spotlight, in
eosinophilic patients, assuming that chronic inflammation
can be related to dysregulation of the epithelial immune
barrier with impairment of protecting mechanisms, caused
by loss of epithelial integrity and failure in the mucociliary
system even though triggers remain to be established.27, 28
We hypothesized that both neutrophilic and eosinophilic
chronic inflammation perpetuated over the years might lead
to mucosal damage and potentially driving the development
of NPs, according to the model suggested by Tos.29 In ad-
dition, we supposed that cytological aspects may be associ-
ated with a different prognostic value. Toward this end we
followed nonallergic patients with selective eosinophilic or
neutrophilic chronic sinonasal inflammation, without evi-
dence of polyps at baseline, and monitoring the occurrence
of NP development over the years.
According to our results, patients with persistent chronic
eosinophilic inflammation in the sinonasal mucosa have a
significantly higher risk of development of NPs, compared
to other non-eosinophilic subgroups of patients, such as
neutrophilic ones and controls. Univariate logistic regres-
sion analysis revealed that eosinophilic patients had a risk
that was 10.55 times higher than controls and 2.76 time
higher than neutrophilic patients. Temporal analyses
with the Kaplan-Meier method revealed that eosinophilic
patients have a significantly lower cumulative probability of
remaining free from NPs compared to neutrophilic patients
(0.63 vs 0.84) and controls (0.63 vs 0.95). These results are
in agreement with literature data demonstrating that cyto-
logical classification of NPs is an important prognostic fac-
tor, since eosinophil predominance in CRS patients has a
negative influence on disease severity.23 Our data confirmed
that even in patients affected by chronic nonallergic rhinitis
the presence of elevated mucosal eosinophilic levels could
represent a prognostic index for more severe disease and a
high risk of NP development. For this reason, we strongly
encourage detecting eosinophilic inflammation in nasal mu-
cosa of these patients. One limitation of our study is that
we considered treated patients and that the percentage of
NP development may be underestimated. Nevertheless, it
is very difficult and probably unethical to study untreated
patients for such a long follow-up time.
Regarding clinical factors we demonstrated that hyper-
eosinophilia, asthma, and AERD in eosinophilic patients
may significantly modify the risk of NP development. Our
data suggest that such clinical factors should always be con-
sidered in the clinical evaluation of eosinophilic patients,
leading to a definition of a large spectrum of severity. In
fact, serum hypereosinophilia increases the OR by 1.18
of developing NPs, asthma increases it by 3.09, AERD
by 4.6, and coexisting asthma and AERD by 6.62. Our
data are in agreement with a previous report by Tokunaga
et al.,30 who presented a new prognostic algorithm for
classification of CRSwNP, including, among other factors,
bronchial asthma and AERD. They demonstrated that these
factors are associated with a poorer course of disease,
meaning significantly higher rates of refractory disease and
recurrence.

865 International Forum of Allergy & Rhinology, Vol. 7, No. 9, September 2017
De Corso et al.

The interrelationship between CRSwNP and asthma is of
great interest and is still under investigation.31, 32 Our data
seem to confirm that asthma in eosinophilic patients corre-
lates with a more severe phenotype. Furthermore, we sug-
gest that asthma in cases of nasal hypereosinophilia should
always be considered early and during follow-up for possi-
ble late onset. Future studies should clarify if early diagno-
sis of nasal hypereosinophilia and early adequate medical
treatment can reduce the onset of asthma.
Previous studies have demonstrated an association be-
tween serum hypereosinophilia and severity of disease in
CRSwNP patients and in particular in terms of higher re-
currence rates.3033 In our case series, multinomial logis-
tic regression analysis showed that patients with hypere-
osinophilia have a slight risk of NP development (OR 1.18),
compared to patients with normal eosinophil blood counts,
without reach a significant statistical value.
Allergy retesting in the eosinophilic group during follow-
up showed that sensitized patients had a percentage of
polyps development higher than negative ones over the
years, although this difference did not reach statistical sig-
nificance (40% vs 25.67%). Moreover, multinomial logistic
analysis showed that the concurrent presence of mast cells
(pathognomonic of allergic infiltrate) at nasal cytology does
not increase the odds of developing NPs. This data seems to
confirm that allergy may play a role as an aggravating factor
in the natural history of CRSwNP, acting as a disease am-
plifier, without a direct etiological trigger.33 We suggest
monitoring allergic status over time, as chronic epithelial
barrier interruption may bring sensitization phenomena,
which has negative prognostic significance in terms of ep-
ithelial barrier failure.
The association between NPs and AERD (in partic-
ular, acetylsalicylic acid [ASA] intolerance) is a topic
debated in the literature. In our series, AERD was higher
in eosinophilic patients than in neutrophilic ones (10% vs
1.8%, respectively). These patients deserve special attention
due to aberrant local eosinophilic inflammatory activity.34
Some authors have hypothesized in previous studies that
patients with nonallergic eosinophilic rhinitis (NARES)
may represent a precursor of Samters syndrome.35 Our
data suggest that eosinophilic inflammation detected in
nonallergic rhinitis patients may represent the early stage
of a very long natural history of eosinophilic CRSwNP in
general, and not only of Samters syndrome.
Conclusions
From a clinical point of view, our findings suggest that
eosinophilic inflammation detected in nonallergic rhinitis
patients represents an early marker for identification of
a more aggressive inflammatory phenotype, with a po-
tential development of NPs. We also demonstrated that
clinical factor such as bronchial asthma, AERD, and ele-
vated eosinophil blood count increase the risk of develop-
ment of NPs differently, leading to a stratification into the
large spectrum of severity in eosinophilic patients. Early
characterization of the inflammatory pattern by nasal cy-
tology seems to be useful to identify patients with a po-
tential risk of development of NPs and, for this reason,
who need more intensive treatment and frequent endo-
scopic follow-up. Early clinical detection of persistent nasal
hypereosinophilia may be important for prevention be-
cause early therapy may potentially postpone the onset
of NPs and prevent comorbidities; however, future stud-
ies are needed to confirm our supposition. Our data sup-
port the prognostic value of cytological aspects of local
chronic inflammation that should be taken into considera-
tion even for CRS patients. A future challenge is represented
by the improvement in differential diagnosis and definition
of etiologic and predisposing factors to identify more ho-
mogeneous patients grouped by physiopathological en-
dotypes that may benefit from individualized, targeted
therapy.

References
1. Tomassen P, Vandeplas G, Van Zele T, et al. In-
flammatory endotypes of chronic rhinosinusitis based
on cluster analysis of biomarkers. J Allergy Clin Im-
munol. 2016;137:14491456.
2. Akdis CA, Bachert C, Cingi C, et al. Endotypes and
phenotypes of chronic rhinosinusitis: a PRACTALL
document of the European Academy of Allergy and
Clinical Immunology and the American Academy of
Allergy, Asthma & Immunology. J Allergy Clin Im-
munol. 2013;131:14791490.
3. De Corso E, Baroni S, Lucidi D, et al. Nasal lavage
levels of granulocyte macrophage colony stimulating
factor and chronic nasal hypereosinophilia. Int Forum
Allergy Rhinol. 2015; 5:557562.
4. De Corso E, Baroni S, Romitelli F, et al. Nasal
lavage CCL24 levels correlate with eosinophils
trafficking and symptoms in chronic sino-nasal
eosinophilic inflammation. Rhinology. 2011;49:174
179.
5. De Corso E, Baroni S, Battista M, et al. Nasal fluid re-
lease of eotaxin-3 and eotaxin-2 in persistent sinonasal
eosinophilic inflammation. Int Forum Allergy Rhinol.
2014;4:617624.
6. Fokkens WJ, Lund VJ, Mullol J, et al. EPOS 2012:
European position paper on rhinosinusitis and nasal
polyps 2012. A summary for otorhinolaryngologists.
Rhinology. 2012;50:112.
7. Wen W, Liu W, Zhang L, et al. Increased neu-
trophilia in nasal polyps reduces the response to
oral corticosteroid therapy. J Allergy Clin Immunol.
2012;129:15221528.
8. Kato A. Immunopathology of chronic rhinosinusitis.
Allergol Int. 2015;64:121130.
9. Ishitoya J, Sakuma Y, Tsukuda M. Eosinophilic
chronic rhinosinusitis in Japan. Allergol Int.
2010;59:239245.
10. Lou H, Meng Y, Piao Y, Wang C, Zhang L, Bachert C.
Predictive significance of tissue eosinophilia for nasal
polyp recurrence in the Chinese population. Am J Rhi-
nol Allergy. 2015;29:350356.
11. Tosun F, Arslan HH, Karslioglu Y, et al. Relationship
between postoperative recurrence rate and eosinophil
density of nasal polyps. Ann Otol Rhinol Laryngol.
2010;119:455459.
12. De Corso E, Battista M, Pandolfini M, et al. Role
of inflammation in non-allergic rhinitis. Rhinology.
2014;52:142149.
13. Meltzer EO, Hamilos DL, Hadley JA, et al. Rhinos-
inusitis: developing guidance for clinical trials. J Al-
lergy Clin Immunol. 2006;118:1761.
14. Hopkins C, Browne JP, Slack R, Lund V, Brown P.
The Lund-Mackay staging system for chronic rhinos-
inusitis: how is it used and what does it predict? Oto-
laryngol Head Neck Surg. 2007;137:555561.
15. Gelardi M, Iannuzzi L, Quaranta N, Landi M, Pas-
salacqua G. NASAL cytology: practical aspects and
clinical relevance. Clin Exp Allergy. 2016;46:785
792.
16. Braido F, Scichilone N, Lavorini F, et al; for In-
terasma Executive Board; ARIA; GA2LEN. Mani-
festo on small airway involvement and management
in asthma and chronic obstructive pulmonary disease:
an Interasma (Global Asthma Association - GAA) and
World Allergy Organization (WAO) document en-
dorsed by Allergic Rhinitis and its Impact on Asthma
(ARIA) and Global Allergy and Asthma European
Network. World Allergy Organ J. 2016;9:37.
17. Rothenberg ME. Eosinophilia. N Engl J Med.
1998;338:15921600.
18. Rosenfeld RM, Andes D, Bhattacharyya N, et al. Clin-
ical practice guideline: adult sinusitis. Otolaryngol
Head Neck Surg. 2007;137:S1S31.
19. Nakayama T, Yoshikawa M, Asaka D, et al. Mu-
cosal eosinophilia and recurrence of nasal polyps
new classification of chronic rhinosinusitis. Rhinol-
ogy. 2011;49:392396.
20. Tan BK, Kern RC, Schleimer RP, Schwartz BS.
Chronic rhinosinusitis: the unrecognized epidemic.
Am J Respir Crit Care Med. 2013;188:12751277.
21. Suzuki H, Wataya H, Takahashi Y, et al. Mechanism
of neutrophil recruitment induced by interleukin-8

International Forum of Allergy & Rhinology, Vol. 7, No. 9, September 2017 866
Predictive value of nasal cytology in NP onset
in chronic sinusitis. J Allergy Clin Immunol. 1996;
98:659670.
22. Suzuki H, Ikeda K. Mode of action of long-term low-
dose macrolide therapy for chronic sinusitis in the light
of neutrophil recruitment. Curr Drug Targets Inflamm
Allergy. 2002;1:117126.
23. Hancer Tecimer S, Kasapoglu F, Demir UL, et al.
Correlation between clinical findings and eosinophil/
neutrophil ratio in patients with nasal polyps. Eur
Arch Otorhinolaryngol. 2015;272:915921.
24. Kern RC, Conley DB, Walsh W, et al. Perspectives
on the etiology of chronic rhinosinusitis: an immune
barrier hypothesis. Am J Rhinol. 2008;22:549559.
25. Hulse KE, Stevens WW, Tan BK, Schleimer RP.
Pathogenesis of nasal polyposis. Clin Exp Allergy.
2015;45:328346.
26. Han JK. Subclassification of chronic rhinosinusitis.
Laryngoscope. 2013;123(Suppl 2):S15S27.
867 International Forum of Allergy & Rhinology, Vol. 7, No. 9, September 2017
27. Zhang N, Van Crombruggen K, Gevaert E, Bachert
C. Barrier function of the nasal mucosa in health and
type-2 biased airway diseases. Allergy. 2016;71:295
307.
28. Lam K, Schleimer R, Kern RC. The etiology and
pathogenesis of chronic rhinosinusitis: a review
of current hypotheses. Curr Allergy Asthma Rep.
2015;15:540.
29. Tos M. Nasal polyps. Curr Opin Otolaryngol Head
and Neck Surg. 1995;3:3135.
30. Tokunaga T, Sakashita M, Haruna T, et al.
Novel scoring system and algorithm for classifying
chronic rhinosinusitis: the JESREC Study. Allergy.
2015;70:9951003.
31. Hirsch AG, Yan XS, Sundaresan AS, et al. Five-
year risk of incident disease following a diagnosis of
chronic rhinosinusitis. Allergy. 2015;70:16131621.
32. Kanani AS, Broder I, Greene JM, Tarlo SM. Corre-
lation between nasal symptoms and asthma severity
in patients with atopic and nonatopic asthma. Ann
Allergy Asthma Immunol. 2005;94:341347.
33. Cao PP, Liao B, Liu Z. Profiling the immunological
characteristics of exacerbation of chronic rhinosinusi-
tis with nasal polyps. Clin Exp Allergy. 2015;45:704
705.
34. Walgama ES, Hwang PH. Aspirin-Exacerbated Res-
piratory Disease. Otolaryngol Clin North Am. 2017
Feb;50(1):8394. https://doi.org/10.1016/j.otc.2016.
08.007. Review.
35. Moneret-Vautrin DA, Hsieh V, Wayoff M, et al. Non-
allergic rhinitis with eosinophilia syndrome a precur-
sor of the triad: nasal polyposis, intrinsic asthma,
and intolerance to aspirin. Ann Allergy. 1990;64:513
518.