Abstract
Bone remodelling is a normal physiological process which occurs in all bones. Hence bone changes should also be detected in undiseased or minimally diseased ethmoids as well as in chronic rhinosinusitis (CRS) patients. To test this hypothesis, we compared ethmoid bone histology between two groups of patients; a study group of CRS patients and a group of patients whose radiological, endoscopic and symptom scores were significantly less when compared to the CRS group. The study group had 75 patients who underwent functional endoscopic sinus surgery for CRS. The control group included 16 patients who had significantly different endoscopic and radiological scores from the study group. On histopathology, the bone harvested from the ethmoid sinuses were grouped as no remodelling activity (Score 1), mild activity (Score 2) and marked activity (Score 3). Thirty-six percent of patients in the study group and 37.5% of patients in the control group had Score 2 and 3 bone changes and the difference was not statistically significant (χ2 = 1.824, p = 0.402). Correlation of bone changes in CRS done with parameters like Lund–Mackay radiological, surgical and symptom scores and Lund–Kennedy endoscopic scores showed no statistical significance. Similar bone changes were detected in CRS patients and the control group. The bone changes seen in histopathology in CRS patients could partly be due to the normal physiological remodelling occurring in all bones.
Keywords: Bone remodelling, Chronic rhinosinusitis, Disease severity, Ethmoid bone, Endoscopy
Introduction
Chronic rhinosinusitis (CRS) is a group of disorders characterised by inflammation of the mucosa of the nose and paranasal sinuses lasting for at least 12 weeks [1]. Despite aggressive therapy, the disease persists in some cases and this has been attributed to persistent inflammation in the underlying bone [2].
The bone changes in CRS have been described as osteitis or neoosteogenesis in literature. The various types of bone histology noted in CRS are osteoblastic activity, bone resorption, periosteal reaction, presence of woven bone and fibrosis. There is a wide variation of the reported prevalence of these changes in CRS with figures ranging from 6.7 to 100% [3, 4]. Studies have also tried to prove the correlation between duration and severity of disease and bone changes in CRS [5–7].
However, bone remodelling is a normal physiological process and occurs in all normal bone [8]. We contend that the undiseased ethmoid bone should also show evidence of bone remodelling. Hence, we compared ethmoid bone histology between two groups of patients; a study group of CRS patients and a group whose radiological and endoscopic findings were significantly different from the CRS group. Besides, we also assessed the Lund–Mackay radiological, surgical and symptom scores along with the Lund–Kennedy endoscopic scores in both groups. We tried to correlate the severity of disease with bone changes [9, 10].
Methods
A prospective longitudinal study was performed in one of our hospitals which is a tertiary referral centre over 2 years. A cohort of 75 consecutive patients with refractory CRS undergoing Functional Endoscopic Sinus Surgery (FESS) constituted the study population. All patients met the criteria established by the Current working definition of CRS as defined by European Position Paper on Rhinosinusitis and Nasal Polyps [11]. The second group of 16 patients who underwent septoplasty and minimal FESS, endoscopic sphenopalatine artery ligation (ESPAL) and cerebrospinal fluid (CSF) rhinorrhea repair comprised the control group. The group of patients who required septoplasty and minimal FESS had no significant endoscopic or Computed Tomography (CT) scan findings, which disqualified them from being included in the study group. Patients with paranasal sinus (PNS) malignancy, acute rhinosinusitis, pregnancy or metabolic bone disease were excluded from the study. Institutional review board approval was obtained.
Proforma was filled up after obtaining written informed consent. Patients were questioned about their symptoms, and scoring was done by Lund–Mackay staging system [10]. In this system, patients used the visual analogue method to score facial pain, headache, nasal block, olfactory disturbance and overall discomfort on a scale of one to ten. The scores were then added to get the total score. Diagnostic nasal endoscopy was performed, and the modified Lund–Kennedy endoscopic score for each patient was determined. A complete coronal CT scan was taken with 3-mm slices, and radiological findings were recorded with the Lund–Mackay staging system [10]. Also, the history of Bronchial asthma and nasal allergy was noted.
Preoperatively, patients were started on antibiotics and antihistaminics. Leukotriene inhibitors were added in cases of nasal allergy and nasal polyposis. No systemic or inhalational steroids were given before surgery. Patients with CRS were graded by the Lund–Mackay surgical score according to the intraoperative findings. In this system, anterior ethoidectomy, middle meatal antrostomy, uncinectomy, posterior ethmoidectomy, sphenoidotomy, middle turbinate reduction and frontal recess surgery are scored as 0 for no surgery and 1 for surgery carried out. The minimum score for each side will be 0 and the maximum 7. The scores of both sides are added together for the total score.
Bone and sinus tissue of the ethmoid sent for histopathological examination after surgery was studied by a single histopathologist to avoid interobserver bias. The bone activity was recorded as no remodelling activity (Score 1) when the bone was completely quiescent with no observable bone formation or resorption, mild activity (Score 2) when scattered osteoid seams with focal areas of resorption were noted and marked activity (Score 3) when numerous and/or thick osteoid seams with obvious osteoblastic activity and numerous resorption bays were noticed [12].
Statistical analysis was done to understand the significance of bone changes in both groups. The strength of the control group was tested by analysing differences in age, duration of symptoms Lund–Kennedy endoscopic and Lund–Mackay radiological, symptom and surgery scores between both groups. The analysis was done by using χ2 Chi-square test, Student’s t test, Spearman’s rank correlation (r) and Mann–Whitney U test. Statistical package version 17 was used. Differences were considered significant if p < 0.05.
Results
Out of 75 patients with CRS in the study group, 76% (n = 58) patients had deviated nasal septum with CRS, 11% (n = 8) patients had nasal polyposis, 3% (n = 2) had Allergic Fungal Rhinosinusitis and 10% (n = 7) had CRS without deviated nasal septum. The second group of 16 patients who underwent septoplasty and minimal FESS, Endoscopic ligation of sphenopalatine artery and CSF rhinorrhoea repair comprised the control group.
Age and Gender
Majority of patients in both groups were below 50 years of age (Table 1). There was no statistical significance when age was compared between the two groups (χ2 = 8.859 p = 0.115). Of 75 patients in study group, 58.6% (n = 44) were males and 41.33% (n = 31) females. Of 16 patients in control group, 62.5% (n = 10) were males and 37.5% (n = 6) were females.
Table 1.
Age representation in the study and control groups
| Age group | Study group | Control group | Total | |||
|---|---|---|---|---|---|---|
| Frequency | Percent | Frequency | Percent | Frequency | Percent | |
| 10–20 | 10 | 13.3 | 0 | 0 | 10 | 11 |
| 21–30 | 18 | 24 | 5 | 31.3 | 23 | 25.3 |
| 31–40 | 19 | 25.3 | 5 | 31.3 | 24 | 26.4 |
| 41–50 | 19 | 25.3 | 2 | 12.5 | 21 | 23.1 |
| 51–60 | 5 | 6.7 | 4 | 25 | 9 | 9.9 |
| 61–70 | 4 | 5.3 | 0 | 0 | 4 | 4.4 |
| Total | 75 | 100 | 16 | 16 | 91 | 100 |
Associated Conditions
Ten patients gave a history of the previous FESS in the study group. Four percent (n = 3) patients had bronchial asthma in the study group, and none in the control group, with no statistical significance between the two groups (χ2 = 1.224, p = 0.269). In the study group, 25.3% (n = 19) had allergy when compared to 12.5% (n = 2) in the control group. There was no statistical significance in the prevalence of allergy between the two groups (χ2 = 1.224, p = 0.269).
Duration of Symptoms
In the study group, duration of symptoms was < 1 year in 60% (n = 45) patients, 1–5 years in 28% (n = 21) and > 5 years in 12% (n = 9). In control group, duration of symptoms was < 1 year in 43.8% (n = 7) patients, 1–5 years in 50% (n = 8) and > 5 years in 6.3% (n = 1). There was no statistical significance between the two groups (χ2 = 3.009, p = 0.222).
Lund–Mackay and Lund–Kennedy Scores
Lund–Kennedy endoscopic and Lund–Mackay radiological and surgery scores, when compared between the two groups, were found to be highly significant (Table 2). However, the symptom scores between the two groups were not significant.
Table 2.
Comparison of Lund–Mackay symptom scores, Lund–Kennedy endoscopic scores, Lund–Mackay radiological and surgery scores in the study and control group
| Lund–Mackay score | Group | Mean | SD | Z |
|---|---|---|---|---|
| Symptom score | Study | 30.29 | 9.948 | 2.346 |
| Control | 23.875 | 7.256 | 0.019 | |
| Endoscopy score | Study | 5.5733 | 3.54 | 4.93 |
| Control | 0.75 | 1.43 | < 0.001 | |
| Radiological score | Study | 11.11 | 5.203 | 6.252 |
| Control | 0.88 | 0.719 | < 0.001 | |
| Surgery score | Study | 9.8 | 2.482 | 4.338 |
| Control | 7.125 | 1.147 | < 0.001 |
Histopathological Bone Changes
In the study group 64% (n = 48) had Score 1 bone changes (Fig. 1), 22.66% (n = 17) had Score 2 changes (Fig. 2) and 13.33% (n = 10) patients had Score 3 changes (Fig. 3), whereas 37.5% (Score 2—12.5% and Score 3—25%) patients in the control group had bone changes. Histopathological bone scores for the two groups were found to be statistically non-significant (χ2 = 1.824, p = 0.402).
Fig. 1.
Microscopic photograph showing histopathological bone Score 1 control case with normal sinus mucosa and underlying thin bony trabeculae (H&E stain ×40)
Fig. 2.
Microscopic photograph showing histopathological bone Score 2 allergic fungal sinusitis with an overlying pool of PAS-positive mucin showing osteoid seams with focal areas of resorption and surrounding epithelial desquamation (PAS stain ×40)
Fig. 3.
Microscopic photograph showing histopathological bone Score 3 extensive new bone formation with plump osteoblast rimming (H&E stain ×40)
Correlations
The histopathological bone score was correlated with age and found to be statistically non-significant (χ2 = 13.334, p = 0.206). Correlation between histopathological bone scores and Lund–Kennedy endoscopic and Lund–Mackay symptom, radiological, and surgery scores (Table 3) were found to be statistically non-significant in both groups.
Table 3.
Correlation between Lund–Mackay surgery, radiological and surgery scores, and Lund–Kennedy endoscopic scores with histopathological scores in study and control groups
| Score | Group | Bone score | n | Mean | SD | F | P |
|---|---|---|---|---|---|---|---|
| Surgery score | Study | 1 | 48 | 9.4792 | 2.57640 | 1.37 | 0.262 |
| 2 | 17 | 10.1176 | 2.34207 | ||||
| 3 | 10 | 10.8000 | 2.09762 | ||||
| Control | 1 | 10 | 7.3000 | 1.25167 | 0.79 | 0.473 | |
| 2 | 2 | 7.5000 | 0.70711 | ||||
| 3 | 4 | 6.5000 | 1.00000 | ||||
| Endoscopy score | Study | 1 | 48 | 5.416 | 3.63 | 0.96 | 0.388 |
| 2 | 17 | 5.176 | 3.30 | ||||
| 3 | 10 | 7 | 3.52 | ||||
| Control | 1 | 10 | 1.2 | 1.686 | 1.371 | 0.288 | |
| 2 | 2 | 0 | 0 | ||||
| 3 | 4 | 0 | 0 | ||||
| Symptom score | Study | 1 | 48 | 29.541 | 10.334 | 3.92 | 0.677 |
| 2 | 17 | 31.352 | 9.532 | ||||
| 3 | 10 | 32.1 | 9.225 | ||||
| Control | 1 | 10 | 25.2 | 5.51 | 1.129 | 0.353 | |
| 2 | 2 | 26.5 | 14.84 | ||||
| 3 | 4 | 19.25 | 7.719 | ||||
| Radiology score | Study | 1 | 48 | 10.81 | 5.242 | 2.222 | 0.116 |
| 2 | 17 | 10.12 | 4.045 | ||||
| 3 | 10 | 14.20 | 6.088 | ||||
| Control | 1 | 10 | 1 | 0.667 | 3.095 | 0.80 | |
| 2 | 2 | 1.5 | 0.707 | ||||
| 3 | 4 | 0.25 | 0.5 |
Discussion
Bone is a metabolically active organ which remodels throughout life. Bone remodelling involves the removal of healthy bone by osteoclasts and deposition of new bone by osteoblasts. Bone remodelling occurs to adjust the bone architecture to the changing mechanical load on the bone and also to maintain calcium metabolism [8].
The term osteitis has been used to define bone changes in CRS. However, this concept has been challenged since no inflammatory infiltrate has ever been detected in the bone in CRS [13]. Moreover, the term osteitis implies a degree of severity of disease, which is not substantiated by the symptoms of the patient [14, 15]. Hence the combination of woven and lamellar bone seen in CRS has been termed as neoosteogenesis.
Many methods have been used to detect neoosteogenesis in CRS. A few studies like ours have looked at the histopathology of bone [4, 12, 16]. Others have attempted to radiologically define osteogenesis in paranasal sinuses. Thickening of bone (> 3 mm) and density of bone > 500 HU has been considered as indicators of neoosteogenesis [3, 17]. Also, increased uptake of Technicium-99 methylene diphosphonate on SPECT bone scan or Tetracycline labelling has been noted [12, 18].
The reported prevalence figures of bone changes in CRS show wide variation. The histopathological studies show bone changes varying from 6.7 to 100% [3, 4]. In our study, 36% of our CRS patients showed bone changes. Telmesani observed bone changes in 52.4% of patients of CRS [16]. Snidvongs has reported similar prevalence as our study; 36% in primary surgeries [6]. Giacchi et al. [19] showed periosteal thickening and varying degrees of bone changes in all 19 patients with CRS.
When the number of sinus walls affected and thickening of the walls were considered together (Global osteitis grading) Georgalas observed an average score of CRS of 9.2 (out of 50), with 33% of patients showing osteitis in the non-operated group [5]. Snidvongs recorded neoosteogenesis in 50% of the 22 primary CRS patients when the bone thickness of > 3 mm was considered as the criterion [13]. However, all bone specimens showed a combination of lamellar and woven bone with varying degrees of neoosteogenesis and osteoblastic activity.
An attempt to analyse the varied incidence of bone changes detected by different methods makes us reflect on the methods of detection. Histopathology and radioisotope uptake studies attempt to study real-time changes in bone, whereas radiological studies of density and bone thickness could be a reflection of the chronicity and historical severity of the disease. Correlation between the two could not be always be proven [13].
Our study did not show a correlation between the severity of disease as assessed by Lund–Mackay scores and histological bone changes. However, Al-Madani et al. [20] have shown a positive correlation between histopathological bone osteitis and Lund–Mackay score in patients with sinonasal polyposis. Radiologically many studies have proven a correlation between Lund–Mackay score and grade of osteitis [5, 6, 20].
The amount of bone remodelling in normal bone is dependent on several factors. The major systemic factors include hormones like parathormone, calcitriol, glucocorticoids and growth hormone. Further, factors such as insulin-like GF, prostaglandins, TGF-β and bone morphogenic protein can influence bone remodelling [8, 21, 22]. While attempting to correlate the severity of disease with bone changes, we need to take into account that CRS is a chronic disease noted for acute exacerbations and remissions. Moreover, most patients with CRS would have received repeated or prolonged courses of antibiotics, antihistamines with or without leukotriene inhibitors, steroids etc. before being subjected to surgery. Hence the inflammatory by-products of CRS along with the type and duration of medical treatment given could well influence bone remodelling in the paranasal sinuses. Further, how long it takes an exacerbation or remission of the disease in the overlying mucosa to influence remodelling in the underlying bone is a matter of conjecture, since no study has addressed this issue.
The bone changes noted in CRS with areas of resorption and new bone formation can also be a part of normal bone physiology. To get good control of CRS patients is difficult due to ethical reasons. However, we had a control group which had significantly different Lund–Mackay radiological and endoscopy scores as compared to the study group. The radiological score in the study group was less than 1.5, which establishes this group as a control group. We could sample the ethmoids in this group of patients since their symptoms warranted minimal FESS. Surprisingly, 37.5% (Score 2—12.5% and Score 3—25%) of controls had bone changes. This was more than the study group. One patient had sphenopalatine artery ligation for epistaxis, with bone Score 3.
Mutijima et al. reported bone changes (osteitis) in 9.5% of ethmoids in the control group of patients who underwent septoplasty alone. The perpendicular plate of ethmoid was sampled and not the labyrinth [4]. Kennedy et al. have reported 25% bone changes in the control group on histology [12]. Our study shows that patients without CRS also show a similar degree of bone changes as patients with CRS.
Our study attempted to analyse the histopathological bone changes in CRS by comparing the results with a control group. This was based on the reasoning that any assessment of neo osteogenesis in the ethmoid bone should be done only in comparison with the normal physiological processes occurring in the bone. However, because of ethical considerations, the ideal control group with no nose or paranasal pathology was not possible. Our control group had one patient each with CSF rhinorrhoea and epistaxis; the rest had DNS with significantly low radiological and endoscopic scores when compared to the study group.
The percentage of patients with CRS in our group with osteitis was low as compared to some studies which have reported much higher rates [20]. One possible reason is that we had only 11% of patients with nasal polyposis and nasal polyposis has been to be associated with histologically proven osteitis [20]. Moreover, only 10 of our patients has a history of previous sinus surgery which is again known to give rise to osteitis.
Bone changes in CRS do not significantly differ from a control group of non-CRS patients. Moreover, the severity of CRS as assessed by Lund–Mackay scoring systems, does not correlate with histopathological bone scores. Hence, we conclude that bone changes seen in CRS patients could well be a part of the normal physiological process occurring in the bone. More studies are required to detect the prevalence and grade of bone remodelling in the normal ethmoid bone.
Even though CRS is associated with changes in the underlying bone, the bone activity is not significant when compared to the control group. The severity of disease as assessed by Lund–Mackay endoscopic, radiological and surgical scoring systems do not correlate with histopathological bone scores in CRS. Hence, we conclude that many of the bony changes seen in histology in CRS patients could be attributed to the remodelling that occurs in normal bone.
Acknowledgements
We thank all the members of Department of ENT and HNS, Kasturba Medical College, Mangalore for their support.
Author Contributions
Conceptualization: Dr. MP, Dr. MNK; Methodology: Dr. SS, Dr. VS, Dr. RP Formal analysis and investigation: Dr. MP, Dr. KB, Dr. AA; writing—original draft preparation: Dr. SS, Dr. SMZ; writing—review and editing: Dr. SS, Dr. SMZ; Supervision: Dr. SS.
Funding
No funds, grants, or other support was received.
Code Availability
Not applicable.
Compliance with Ethical Standards
Conflicts of interest
The authors declare that they have no conflict of interest.
Availability of Data and Materials
Data is retained by the corresponding author and will be available if required.
Consent for Publication
Not applicable.
Ethics Approval
All procedures performed in this study conformed to the ethical standards of the institutional ethical committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed Consent
Informed consent was obtained from all individual participants included in the study.
Footnotes
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Data is retained by the corresponding author and will be available if required.