Advances in Cellular and Molecular Otolaryngology

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Osteitis in chronic rhinosinusitis: a

histopathological study of human ethmoid bone
remodeling in allergic versus non-allergic chronic
rhinosinusitis

Eugene Mutijima, Philippe Delvenne & Amr E. El-Shazly

To cite this article: Eugene Mutijima, Philippe Delvenne & Amr E. El-Shazly (2014) Osteitis in
chronic rhinosinusitis: a histopathological study of human ethmoid bone remodeling in allergic
versus non-allergic chronic rhinosinusitis, Advances in Cellular and Molecular Otolaryngology, 2:1,
23504, DOI: 10.3402/acmo.v2.23504

To link to this article: https://doi.org/10.3402/acmo.v2.23504

© 2014 Eugene Mutijima et al.

Published online: 08 Jan 2014.

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ORIGINAL RESEARCH ARTICLE
æ

Osteitis in chronic rhinosinusitis:

a histopathological study of human
ethmoid bone remodeling in allergic
versus non-allergic chronic rhinosinusitis
Eugene Mutijima, Philippe Delvenne and Amr E. El-Shazly*
Laboratory of Experimental Pathology, Experimental Rhinology Unit, Department of Otolaryngology,
Liège University Hospital (Centre Hospitalier Universitaire de Liège), Liège, Belgium

Background: Chronic rhinosinusitis (CRS) is a disease characterized by inflammation of the mucosa lining
the paranasal sinuses; however, recent evidence also indicates the involvement of the sinus bones in the
inflammatory process. CRS is a disease with different phenotypes; nonetheless, the characterization of osteitis
in the different CRS phenotypes is poorly characterized. Herein, we report on osteitis in two main phenotypes
of CRS: a group allergic to aeroallergens who suffers from long-lasting upper airway allergy, and the CRS
group with no upper airway allergy.
Patients and methodology: A total of 51 patients (23 females and 28 males, with a mean age of 39.03913.4)
who underwent surgery in our university hospital contributed to this study by providing bone samples from
the ethmoid bone. They were divided into three groups: group I is patients who underwent septoplasty with
or without partial inferior turbinectomy, and they acted as the control group; group II is patients who
underwent operation for non-allergic CRS (NACRS); and group III is patients who underwent operation for
allergic CRS (ACRS). Sections of the decalcified ethmoid bone were stained with hematoxylin and eosin for
histological evaluation for osteitis (periosteal thickening and remodeling, osteoblastic and osteoclastic
activity, and osteomyelitis and bone destruction) that was graded from 0 to IV, where grade 0 is normal
histology and grade IV is frank osteomyelitis and bone destruction.
Results: Descriptive histology of the ethmoid bone analysis demonstrated osteitis of different grades in
patients suffering from CRS with or without upper airway allergy. In the ACRS group, 80% demonstrated
grade I osteitis, and 20% grade II. However, 11.11% of the NACRS group demonstrated normal bone
histology, and 88.88% demonstrated osteitis: 33.33% demonstrated grade I, 50% grade II, and 5.5% grade III.
The control group showed normal bone histology in 90.47% and grade I osteitis in 9.52%. The mucosal
disease was higher in the grade of inflammation than the osteitis in both CRS groups (II and III). There was
no correlation between the mucosal and bone grade of inflammation in both CRS groups.
Conclusion: Herein, we show evidence of osteitis in ACRS and confirm the presence of a higher grade osteitis
in the NACRS patients. This sinus bone remodeling may contribute to the chronicity of the disease and
carries special consideration in the treatment of CRS.
Keywords: allergic rhinitis; sinusitis; ethmoid osteitis; periosteal thickening; osteoclasts; osteoblasts

*Correspondence to: Amr E. El-Shazly, Laboratory of Experimental Pathology, Experimental Rhinology

Unit, Department of Otolaryngology, Liège University Hospital, Liège, Belgium, Email: ashazly@chu.ulg.ac.be

Received: 25 October 2013; Revised: 20 November 2013; Accepted: 22 November 2013; Published: 8 January 2014

n the field of rhinology, the majority of studies focus with CRS are radiologically assessed with computed

I on mucosal immunology of the nose without giving

attention to the underlying bones. Recent evidence
indicates that the inflammation of chronic rhinosinusitis
(CRS) is beyond the mucous membrane and involves the
underlying bone of the paranasal sinuses as well. Patients
tomography (CT) scans that often reveal areas of
increased bone density and irregular thickening of the
sinus walls. This could explain the recurrence of the
mucosal disease after surgical treatment and may indicate
that these osteitic lesions act as the source of the chronic

Advances in Cellular and Molecular Otolaryngology 2014. # 2014 Eugene Mutijima et al. This is an Open Access article distributed under the terms of the 1
Creative Commons Attribution-Noncommercial 3.0 Unported License (http://creativecommons.org/licenses/by-nc/3.0/), permitting all non-commercial use,
distribution, and reproduction in any medium, provided the original work is properly cited.
Citation: Advances in Cellular and Molecular Otolaryngology 2014, 2: 23504 - http://dx.doi.org/10.3402/acmo.v2.23504
(page number not for citation purpose)
Eugene Mutijima et al.
inflammation (1
3). Therefore, proper understanding of
the magnitude of bone involvement in CRS inflammation
is mandatory for proper treatment. Renato et al. (4)
studied the ethmoid bone from 20 patients undergoing
endoscopic sinus surgery for CRS, and they reported that
the histopathological findings suggested associated ostei-
tis of the underlying ethmoid bone. In a study of the
impact of osteitis in CRS on disease severity, the authors
found osteitis to be associated with worse baseline
measures of disease severity and inflammation (5).
Georgalas et al. (6) found that in patients with recalci-
trant CRS who have undergone multiple surgeries in the
past, the incidence of osteitis can be as high as 64%.
Although it seems certain from the evidence mentioned
so far that osteitis is an effector factor in CRS patho-
physiology, it is surprisingly an area of research that has
not been explored sufficiently. Moreover, no reports have
looked at osteitis in CRS patients with atopy or allergy
versus CRS patients without allergy. Therefore, our aim
in the current study was to evaluate the grade of osteitis
in the ethmoid bone from patients who had endoscopic
sinus surgery for their CRS and to look at the differences
between osteitis in atopic patients versus non-atopic ones.
We also correlated the grade of osteitis to the grade of
mucosal disease to have an overall evaluation of the
inflammatory process in the studied CRS groups. Herein,
we show that the ethmoid bone from Allergic CRS
(ACRS) patients demonstrated osteitis; however, the
grade of this osteitis was less than that of the non-allergic
CRS (NACRS) patients. Interestingly, although both
groups had mucosal inflammation, there was no correla-
tion in the inflammation grading between the bone and
mucosa in both groups (i.e., ACRS and NACRS).
Materials and methods
Patients
A total of 51 patients, who had not undergone operation
before for CRS, contributed to this prospective study.
There were 23 females and 28 males, with ages ranging
between 21 and 66 years, and a mean age of 39.03913.4
years. They were divided into three groups: group I
comprised 21 control patients (M:F8 13:8) who under-
went operation for septoplasty with or without turbino-
plasty of the inferior turbinates. The deviated part of
the perpendicular plate of the ethmoid was studied as a
control for the ethmoid bone’s osteitic activity from
CRS patients. These patients were suffering from neither
allergy nor CRS. Group II was 19 patients (M:F8 9:10)
who underwent operation for CRS with or without
nasal polyps affecting both sides. These patients were
neither allergic to aeroallergens nor atopic, as judged
by skin tests and a radioallergosorbent test (RAST).
The ethmoid bone removed during ethmoidectomy was
studied for osteitic activity. Finally, group III was 11
2
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Citation: Advances in Cellular and Molecular Otolaryngology 2014, 2: 23504 - http://dx.doi.org/10.3402/acmo.v2.23504
patients (M:F8 6:5) who underwent operation for CRS
with or without nasal polyps affecting both sides, and
who were having long-lasting allergic rhinitis that was
suboptimally controlled and that resulted in CRS as a
complication of their nasal allergy. The ethmoid bone
removed during ethmoidectomy was studied for osteitic
activity. Patients with recalcitrant CRS or allergic fungal
sinusitis were excluded from the current study.
Bone preparation for histopathology
The bone specimens were fixed in 10% neutral buffered
formalin for more than 24 h, routinely decalcified in
formic acid solution, and embedded in paraffin. Sections
of 4 mm of each specimen were stained with hematoxylin
and eosin for histological evaluation.
The evaluation was performed in a double-blinded
fashion for osteitis grading. We used a bony grading as
used by Biedlingmaier et al. (7), who graded the osteitis
into five grades: grade 0 for normal bone; grade I for
periosteal thickening; grade II as in I, in addition to
osteoblastic and osteoclastic activity with bone resorp-
tion and/or remodeling; grade III as in II, in addition to
wide osteoid matrix; and grade IV is frank osteomyelitis,
leucocytes infiltration, and bone destruction. We tried
to count the number of inflammation cells in bone
specimens, but that was not possible in the majority of
cases.
For the mucosal grading, we also adopted the same
grading system as Biedlingmaier et al. (7). Four grades
was defined: grade 0 is for normal histology, grade I is for
mild chronic inflammatory cells infiltrate, grade II is for
mild to moderate scattered chronic inflammatory cells
infiltrate, grade III is for moderate amounts of chronic
inflammatory cells infiltrate, and grade IV is for severe
significant amounts of chronic inflammatory cells infil-
trate in the lamina propria. The evaluation was per-
formed utilizing a Leitz Laborlux D microscope at 40
(high-power field).
Statistical analysis
The correlation between mucosal and bone inflammation
was evaluated by Pearson’s test using GraphPad Prism
statistical software, version 5.
Results
Osteitis in different studied groups
A descriptive histology of one patient representative of
each studied group is demonstrated in Fig. 1. Fig. 1A
represents the histology from one control patient who
underwent septoplasty with partial inferior turbinectomy,
and it shows normal histology. In contrast, the histology
from the ACRS group (Fig. 1B) demonstrated mixed
inflammatory cells infiltrating the lamina propria, in-
cluding numerous eosinophils, with thick periosteum
around the lamellar bone; and the histology from the
 Osteitis in chronic rhinosinusitis

Fig. 1. Descriptive histology of the ethmoid bone and nasal mucosa. (A) Control: thinner lamina propria with few vessels, thin
trabeculae of mature lamellar bone, and a very thinned periosteum. (B) Allergic chronic rhinosinusitis (ACRS): mixed inflammatory
cells infiltrating the lamina propria, including numerous eosinophils (black arrow), with thick periosteum around the lamellar bone
(blue arrow). (C,D) Non-allergic chronic rhinosinusitis (NACRS): (C) severe inflammatory cells, predominantly lymphocytes and
plasma cells (black arrow); and (D) osteoid bone interconnected haphazardly (red arrow) with osteoblastic rim (blue arrow) and focal
osteoclastic activity (black arrow).

NACRS group showed severe inflammatory cell infil-
trate, predominantly lymphocytes and plasma cells, with
osteoid bone interconnected haphazardly with increased
osteoblastic and osteoclastic activity.
Grade of osteitis in different studied groups
All 51 patients’ histological slides were reviewed in a
blinded fashion by the same investigator to grade the
osteitis. Afterward, we compared the grading of osteitis in
each studied group. As seen in Fig. 2A, histological
analysis of the ethmoid bone from control group who
underwent septoplasty showed normal bone histology in
90.47% of cases, and 9.52% demonstrated grade I osteitis.
In the NACRS group, 11.11% demonstrated normal
bone histology, 33.33% demonstrated grade I osteitis,
50% demonstrated grade II osteitis, and 5.5% demon-
strated grade III osteitis (Fig. 2B). In the ACRS group,
100% of patients showed osteitis: 80% were grade I and
20% were grade II (Fig. 2C).
Correlation between bone and mucosal
inflammation in CRS
We next investigated whether there is a correlation
between the bone and mucosa grade of inflammation. In
the NACRS group, the mucosal grading was as follows:
5.55% showed grade 0, 16.66% showed grade I, 27.77%
showed grade II, 16.66% showed grade III, and 33.33%
showed grade IV. In comparison, the ACRS group
mucosal grading was as follows: 30% showed grade I,
20% showed grade II, 40% showed grade III, and 10%
showed grade IV. As seen in Fig. 3, there was a higher
grade of mucosal inflammation over bone inflammation
in both CRS groups. However, there was no correlation
between the grade of bone and mucosal inflammation in
each studied group.
Discussion
Bone infection in sinusitis has been evident since earlier
studies on animal models of severe sinusitis in rabbits
that demonstrated a periosteal reaction of fibrosis, bone
degradation, and neo-osteogenesis, starting as early as
4 days after sinus infection and also able to affect the
contralateral side that was not infected (1, 8
10).
Histomorphometric studies also demonstrated ethmoid
bone remodeling in patients with CRS (11). Bone
remodeling involves osteoblast and osteoclast activity.
The former function is to produce type I collagen and the
components of the bone matrix, including calcifying the
matrix and controlling the osteoclast activity. However,
osteoclasts solubilize the calcified matrix, which in turn
stimulates osteoblast proliferation. Therefore, distur-
bance of the delicate balance between the dynamics and
activity of these cells that take place under normal
conditions may significantly affect the process of bone
remodeling. This could be seen in inflammation since
inflammatory cytokines can influence osteoblast activity
(12).

Citation: Advances in Cellular and Molecular Otolaryngology 2014, 2: 23504 - http://dx.doi.org/10.3402/acmo.v2.23504 3

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Eugene Mutijima et al.
Fig. 2. The grading of osteitis in the different studied groups: (A) group I (control), (B) group II (NACRS), and (C) group III (ACRS).
The y-axis demonstrates the number of patients, and the x-axis represents the grade of osteitis.
In the current study, we investigated osteitis in two
broad phenotypes of CRS, the non-allergic group that is
biased to the TH1 cytokine profile and the allergic group
that is biased to the TH2 cytokine profile. Herein, we
demonstrated increases in osteoblastic and osteoclastic
bone activity that resulted in osteitis of the ethmoid bone
with its remodeling from patients with non-recalcitrant
CRS. This is consistent with earlier reports that demon-
strated osteitis of the ethmoid bone in CRS patients.
However, we also demonstrated the first evidence that in
ACRS, the ethmoid bone also undergoes remodeling. The
majority of osteitis witnessed in the allergic group (80%)
was in the form of periosteal thickening, and in 20%
there were also increases in osteoblast and osteoclast
activity with bone remodeling. Interestingly, osteitis was
present in all studied patients (100%) in the allergic group.
However, 88.88% from the NACRS group showed differ-
ent grades of osteitis that were most striking in regard to
periosteal thickening and osteoblastic and osteoclastic
activity; there was bone remodeling in 50% of cases, and
5.5% also demonstrated osteoid bone that was intercon-
nected haphazardly. We did not see any severe-grade
osteitis with frank osteomyelitis and bone destruction
(i.e., grade IV) in our studied groups; perhaps this is
4
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Citation: Advances in Cellular and Molecular Otolaryngology 2014, 2: 23504 - http://dx.doi.org/10.3402/acmo.v2.23504
because we excluded patients with recalcitrant CRS from
the current study as well as patients with allergic fungal
sinusitis. Of note, in the control group, two out of the 21
studied patients showed grade I osteitis. When we reviewed
their clinical picture, we found that these two patients also
underwent partial inferior turbinectomy for associated
chronic hypertrophic rhinitis, but no CT scans for them
were available. Therefore, it is difficult to comment on their
osteitis, which may be due to associated mucosal sinus
changes. Another explanation may be that in nonspecific
rhinitis, the underlying bone also may be involved in the
inflammatory process. This requires further studies to
prove or disprove.
When we compared the mucosal inflammation to bone
inflammation in both CRS groups, there was higher a
grade of mucosal inflammation than of bone inflamma-
tion, reflecting a higher inflammatory index in general in
the NACRS group over the ACRS group. However,
there was no correlation between the grade of mucosal
inflammation and that of bone inflammation in each
studied group. This interestingly finding may indicate that
although CRS patients demonstrate mucosal and bone
inflammation, the severity of inflammation between the
mucous membrane and bone is not correlated, and the

Fig. 3. (A) Correlation between mucosal grading and bone grading in allergic group; (B) correlation between mucosal grading and bone
grading in non-allergic group.
mucosal and bone inflammation from the NACRS group
may be higher in grade than that of the ACRS group.
The definition of chronic sinusitis over the years was
limited to chronic inflammation of the mucous membrane
lining the paranasal sinuses. The terminology was changed
recently to ‘chronic rhinosinusitis’ since the inflammatory
process of the mucous membrane of the nasal cavity often
also involves the paranasal sinuses. Herein, we also
demonstrated the involvement of the underlying ethmoid
bone in the process of inflammation that was not
correlated to the mucosal inflammation. Our results
together with those of previous investigators strongly
point to the more appropriate definition of CRS as an
inflammatory process involving the mucous membranes of
the nasal cavity and paranasal sinuses and the underlying
bone. This is also true for patients suffering from ACRS.
The higher osteitis grade seen in the NACRS group over
the ACRS group may reflect a specific cytokine profile,
since the current thinking is that CRS is biased toward the
TH1 cytokine profile and allergy biased to TH2 cytokine
profile. Another possible explanation of the differences in
the grade of osteitis between both groups could be an extra
Citation: Advances in Cellular and Molecular Otolaryngology 2014, 2: 23504 - http://dx.doi.org/10.3402/acmo.v2.23504
Osteitis in chronic rhinosinusitis
factor such as the type and virulence of bacterial infection.
This is currently under investigation in our laboratory.
In conclusion, herein we demonstrate bone remodeling
in patients suffering from ACRS and confirm the bone
involvement with a higher grade osteitis in CRS without
allergy. These results may open channels for further
research exploring the exact mechanisms by which nasal
and paranasal mucosal inflammation reaches the under-
lying bone and how to treat osteitis in nasal and
paranasal inflammation.
Conflict of interest and funding
The authors have not received any funding or benefits from
industry or elsewhere to conduct this study.
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