The potential role of hyaluronan in minimizing symptoms and preventing exacerbations of chronic rhinosinusitis

The potential role of hyaluronan in minimizing symptoms
and preventing exacerbations of chronic rhinosinusitis
Manuele Casale, M.D.,1 Lorenzo Sabatino, M.D.,1 Valeria Frari, M.D.,1 Francesco Mazzola, M.D.,1
Rosa Dell’Aquila, M.S.,1 Peter Baptista, M.D.,2 Ranko Mladina, M.D.,3 and Fabrizio Salvinelli, M.D.1
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ABSTRACT
Background: This study was designed to prospectively evaluate the role of nebulized hyaluronic acid (HA) given for 10 days/mo over 3 months as adjunct
treatment to minimize symptoms and preventing exacerbation of chronic rhinosinusitis (CRS).
Methods: Thirty-nine eligible patients were randomized to receive nebulized 9-mg sodium hyaluronate nasal washes plus saline solution (21 patients) or
5 mL of saline alone (18 patients), according to an open-label, parallel-group design, with blind observer assessment. A questionnaire about main CRS
discomfort and nasal endoscopy for mucous discharge and/or mucosal edema of nasal cavities was used to assess primary outcomes of treatments. Secondary
outcome measures included side effects and satisfaction.
Results: HA significantly improved quality of life in CRS patients according to the CRS questionnaire (16⫾ 3.72 versus 11.52 ⫾ 4.28; p ⬍ 0.001), contrary
to saline group scores (18.92 ⫾ 3.09 versus 18.21 ⫾ 3.21; p ⫽ 0.55). The HA group showed significantly reduced osteomeatal edema (2.42 versus 1.52; p ⬍
0.001) and secretions (0.95 versus 0.42; p ⬍ 0.001), whereas there was no statistically significant difference in the saline group. The compliance to the treatment
was similar in both groups and no side effects were recorded.
Conclusion: The results of this study suggested that intermittent treatment with topical 9-mg sodium hyaluronate plays a role in minimizing symptoms
and could prevent exacerbations of CRS.
(Am J Rhinol Allergy 28, 345–348, 2014; doi: 10.2500/ajra.2014.28.4045)
C
hronic rhinosinusitis (CRS) is one of the most common chronic
diseases in the United States affecting an estimated 35 million
people. From 1985 to 1992, sinusitis was the fifth leading cause of
antibiotic prescriptions. The health care cost is estimated at $73 million. Moreover, CRS is one of the most common causes of absence
from work and for visits to a family doctor’s office.1
The different courses of antibiotics that usually are prescribed to
patients suffering from CRS cause a negative effect on quality of life;
furthermore, there are limited cases showing the benefits of using
topical antibiotics in nasal irrigation.2,3
Clinicians should work in developing treatment strategies that can
minimize symptoms, promote recovery, and prevent CRS recurrences.4 Saline nasal irrigation is proposed for secondary prevention
after sinus surgery, but limited evidence suggests that saline nasal
irrigations relieve sinonasal symptoms and may reduce reliance on
other medications.5
Hyaluronic acid (HA) is a naturally occurring, nonsulfated glycosaminoglycan with a high molecular weight of 400–20,000,000 Da. HA
structure consists of polyanionic disaccharide units of glucuronic acid
and N-acetyl-glucosamine connected by alternating b1-3 and b1-4
bonds. It is a linear polysaccharide of the extracellular matrix of
connective tissue, synovial fluid, embryonic mesenchyma, vitreous
humor, skin, and many other organs and tissues of the body. The
main function of HA includes tissue healing including activation and
moderation of the inflammatory responses, promotion of cell proliferation, migration, and angiogenesis.6
The aim of this study was to evaluate the role of HA in minimizing
the symptoms and preventing exacerbations of CRS compared with
simple nasal washes with saline solution.
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METHODS AND MATERIALS
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Thirty-nine consecutive adult patients with CRS according to recent
guidelines7 have been prospectively enrolled from October 2012 to
January 2013, according to an open-label, parallel-group design. We
have performed full endoscopy and computed tomography scans on
all enrolled patients.
Patients with previous sinonasal surgery, those with computed
tomography evidence of anatomic obstructions (severe septal deformity and concha bullosa), primary and secondary immunodepression, septal defects, nasal polyposis and mucocele, benign or malignant tumors of the nasal cavity, and a history of previous nasal
radiotherapy were excluded; in addition, we excluded patients with
diabetes mellitus, recent peroral or systemic steroid use, coagulation
disorders, cystic fibrosis, cardiac pacemakers, uncontrolled hypertension, major psychiatric disorders, and pregnancy.
All included subjects were randomized and divided into two
groups.
HA Group
This group consisted of 21 patients of whom 8 were female and 13
were male subjects, of a mean age of 44 years (range, 30–63 years).
They have been treated with HA (Yabro, IBSA Farmaceutici, Lodi,
Italy) 3 mL of HA is dissolved in 2 mL of isotonic solution twice a day
for 10 days per months over 3 months through Rinowash (Air Liquide
Medical System S.p.A., Bovezzo, Italy), a nebulizer designed to treat
upper airway structures, creating nebulization of particles with a mean
diameter ⬎10 micron for 10 days a week for 3 months, and in the last 20
days of the month only saline solution (5 cc) twice a day (Fig. 1 a).
Saline Group
1
From the Department of Otolaryngology, University Campus Bio-Medico, Rome,
Italy, 2Department of Otolaryngology, University of Navarra, Pamplona, Spain, and
3
Department of Otolaryngology, University of Zagreb, Croatia
The authors have no conflicts of interest to declare pertaining to this article
Address correspondence to Manuele Casale, M.D., Ph.D., Department of Otolaryngology, Campus Bio-Medico University, School of Medicine, Via Alvaro del Portillo 21,
00128 Rome, Italy
E-mail address: [email protected]
Copyright © 2014, OceanSide Publications, Inc., U.S.A.
This group consisted of 18 patients of whom 8 were female and 10
male subjects, with a mean age of 38 years (range, 34–58 years). They
received normal saline (5 cc) nasal nebulization (Rinowash) twice a
day for 3 months (Fig. 1 b).
All patients were evaluated with blind observer assessment at the
beginning and 3 months after the treatment. We also analyzed the
cost, time, satisfaction, and compliance of both groups.
The study protocol was approved by the Research Ethics Committee
at our institution and every patient signed a written informed consent.
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345
a
HA group
HA
0
10
30
0
40
60
70
90 days
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Saline
b
Saline group
0
T
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Figure 1. Therapeutic schedule in (a) hyaluronic acid (HA) group and (b) saline group.
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Evaluation
The patients were asked to mark the severity of the main CRS
symptoms by a CRS questionnaire about main CRS symptoms shown
in Fig. 2. Patients recall how bothered they have been by their symptoms during the previous weeks and to respond to each question on
a 4-point scale (0 ⫽ not impaired at all; 4 ⫽ severely impaired; Fig. 3).
The overall score is the mean of all 16 responses and the individual
domain scores are the means of the items in those domains.
Endoscopic nasal examination was performed by a flexible nasal
fiberendoscope. The findings were scored with respect to middle
turbinate edema (0 ⫽ none, 1 ⫽ mild, 2 ⫽ moderate, and 3 ⫽ severe)
346
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90 days
Figure 2. Chronic rhinosinusitis (CRS) questionnaire.
and nasal secretions (0 ⫽ none, 1 ⫽ severe; Fig. 4). All patients were
evaluated by a blind observer at the beginning and after 3 months.
Statistical Analysis
Statistical analysis was performed using the Statistical Package for
Social Sciences Software (SPSS 10.0 for Windows; SPSS Inc., Chicago,
IL). Data are shown as means and SDs. Parametric (Student’s t-test)
and nonparametric (Wilcoxon test for paired data and Mann-Whitney
U test for nonpaired data) tests were used to compare different
values. Our criterion for statistical significance was set at value of p ⬍
0.05 (two-tailed).
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CRS SCORE
20
p= NS
18
p<0,001
16
14
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12
10
8
6
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4
2
0
Pre
Figure 3. Rhino-sinusal symptoms graded
using chronic rhinosinusitis (CRS) Questionnaire. HA, hyaluronic acid.
Post
Pre
Post
Saline group
HA group
T
Endoscopic nasal score
3
P<0,001
O
N
2.5
2.42
2
1
5
1.5
P=NS
2.55
2.22
1.52
P<0,001
P=NS
1
1
0 95
0.95
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1
0.5
0.42
0
Pre
Post
Pre
HA group
Figure 4. Endoscopic nasal score from 0
(none) to 3 (severe).
Post
Saline group
Edema
Secreon
RESULTS
Endoscopic Nasal Score
Thirty-nine patients were included in the study. The demographic
data of the two groups are summarized in Table 1.
The reduction of the mucosal edema of the middle turbinate has been
statistically significant in the HA group, whereas it was not the case in
the saline group (2.42 versus 1.52; p ⬍ 0.001). The same goes for nasal
secretions (0.95 versus 0.42; p ⬍ 0.001), and there was no statistically
significant difference in the saline group after treatment (Fig. 2).
Impact on CRS Symptoms
As shown in Fig. 1, although the HA group had higher pretreatment CRS symptoms score (p ⫽ 0.02), the HA significantly improved
quality of life in patients with sinonasal symptoms in the CRS questionnaire score (16 ⫾ 3.72 versus 11.52 ⫾ 4.28; p ⬍ 0.001), unlike the
saline group that showed posttreatment CRS questionnaires similar to
the pretreatment questionnaire (18.92 ⫾ 3.09 versus 18.21 ⫾ 3.21; p ⫽
0.55).
Other Parameters
Both groups showed good patient satisfaction, but the compliance
in the HA group was lower than that of the saline group (73% versus
85%), probably because of the longer average time of administration;
in particular, the mean time of administration of HA is slightly longer
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347
tion; new devices and additional studies are advisable for topical
sinonasal therapy.18
Because CRS and recurrent acute rhinosinusitis have periods of
symptom exacerbation, clinicians and patients should work together
in developing treatment strategies that can minimize symptoms, promote recovery, and prevent recurrences.4
HA could be an adjunct treatment of symptoms and exacerbations
of CRS in comparison with placebo and is well tolerated in improving
nasal mucociliary function, decreasing nasal mucosal edema and
secretion.
Table 1 The demographic data of the two groups
HA Group 21
Saline Group 18
44 (30–63)
13/8
0.23
38 (34–58)
10/8
0.32
Mean age (range), yr
Male/female
Allergy test positive (% positive)
HA ⫽ hyaluronic acid.
than the saline group (2 minutes versus 4 minutes, respectively). No
adverse outcomes related to HA were recorded in either group.
Although today HA is widely used in many branches of medicine,
this is the first pilot study showing that intermittent nasal nebulizations with HA can be a new strategy for secondary prevention of CRS
or recurrent acute rhinosinusitis. Additional studies are necessary to
confirm our encouraging results.
DISCUSSION
Today HA is widely used in many branches of medicine, especially
in esthetic medicine where it is used as a filling material for folds and
creases as well as enlarging whole body parts (lips, breasts, buttocks,
etc.). Contraindications or interactions with drugs are not reported.
The form of the drug that we used in our study was a mixture of
saline solution and HA, a natural constituent of human tissues. Millions of successful injections performed around the world make it a
product characterized by a high level of safety. HA is a major component of many extracellular matrices and plays a central role in the
homeostasis of physiology in upper and lower airways.8
HA, unlike other materials, exhibits better water absorption and
was successfully used in atrophic rhinitis. When topically administered, HA promotes rhino-sinusal remodeling and it may be effective
in functional recovery and in the prevention of recurrence of CRS
after endoscopic sinus surgery9 and it could be considered a supportive treatment for a faster improvement of nasal respiration, also
minimizing patients’ discomfort in postoperative nasal surgery.10,11
Risk factors of recurrent sinusitis involve upper respiratory infections, day care attendance, and exposure to tobacco smoke.12 as well
as sinonasal anatomic abnormalities, including septal deviation, choanal atresia, polyps, and hypoplasia of sinuses. Furthermore, several
systemic disorders can facilitate the development of CRS, such as
allergic rhinitis, gastroesophageal reflux disease, cystic fibrosis, primary ciliary dyskinesia, and immunodeficiency diseases.13
The medical treatment of chronic sinusitis is even more empiric and only
partially accredited, including antibiotics (amoxicillin/clavulanate for 10–21
days), intranasal corticosteroids, and decongestants: the role of bacterial
infection and the relevance of antibiotic therapy are controversial.14
Although the efficacy is unproven, short-term topical steroids or
cromolyn sodium have shown some benefit, mainly in patients with
allergic symptoms; long-term therapy (ⱖ3 months) with intranasal
corticosteroids may cause overinfection sustained by Pseudomonas
aeruginosa.15 Similarly, for other anti-inflammatory agents commonly
used in clinical practice (e.g., antihistamines), there is evidence that
supports their efficacy in chronic as well as in acute sinusitis.
Hyaluronan plays an important role on respiratory epithelial cells
and gland serous cells of the nasal mucosa by increasing the function
of mucociliary clearance by the epithelial surface, hastening the processes involved in wound healing and repairing mucosal surfaces.
When high molecular weight HA is delivered to the nasal mucosa, it
is broken down by reactive oxygen species to form low molecular
weight fragments. These stimulate a receptor for HA-mediated motility, which has no transmembrane domain but is physically associated with “recepteur d’origine nantais” at the apex of ciliated cells.
Macrophage-stimulating protein is an agonist of “recepteur d’origine
nantais” and is known to increase the ciliary beat frequency.16
To avoid relapses, daily saline irrigations are recommended to clear
the secretions and enhance mucociliary transport, relieving sinonasal
symptoms and reducing reliance on other medications17; this practice
is commonly used and supported by experts.4 The Rinowash device
also allows the HA solution to reach the osteometal complex, ameliorating sinus drainage compromised by sinus and nasal inflamma-
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CONCLUSION
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