A Randomized Clinical Trial of Elemental Zinc Add-on Therapy on Clinical Outcomes of Patients with Chronic Rhinosinusitis with Nasal Polyposis (CRSwNP)

authors:

avatar Nader Akbari Dilmaghani a , b , * , avatar Nadereh Alani a , avatar Sepideh Fazeli a

Department of Otolaryngology, Head and Neck Surgery, Loghman Hakim Educational Hospital, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Hearing Disorders Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Iranian Journal of Pharmaceutical Research : IJPR: Vol.18, issue 3; 1595-1601
article type: Original Article
received: November , 2016
accepted: May , 2018
DOI: https://doi.org/10.22037/ijpr.2019.1100767

how to cite: Akbari Dilmaghani N, Alani N, Fazeli S. A Randomized Clinical Trial of Elemental Zinc Add-on Therapy on Clinical Outcomes of Patients with Chronic Rhinosinusitis with Nasal Polyposis (CRSwNP). Iran J Pharm Res. 2019;18(3):e126204. https://doi.org/10.22037/ijpr.2019.1100767.

Abstract

Recent studies suggest a relationship between zinc deficiency and inflammation. In the present study, we studied the effect of oral zinc supplementation on clinical improvement of chronic rhinosinusitis with nasal polyposis. In this single-blind randomized controlled trial, 44 patients with chronic rhinosinusitis with polyposis referring to ENT clinic of the Loghman Hakim hospital during 2013-2014 were randomly allocated in two groups. The treatment group (n = 28) was treated with a four-drug fixed-dose regimen (FD_FDR) consisting of oral dexamethasone (0.02 mg/kg), fluticasone nasal spray, fexophenadine 60 mg daily, montelukast 10 mg daily plus 220mg zinc sulfate capsules containing 55 mg elemental zinc, b.d., and the control group (n = 16) received the FD_FDR without supplemental zinc, for six weeks. After sixth week, two groups were compared regarding clinical outcomes based on theSNOT20 (Sinonasal outcome test) questionnaire, the general health questionnaire (SF12), the Lund-Mackay, and the Lund-Kennedy scoring systems. In the treatment group, serum zinc levels were significantly increased compared to those at the baseline (1.33 fold-increase; p = 0.0002). Within groups analysis revealed a significant reduction (p < 0.01) in LM and LK in both treatment (55% LM; 50% LK) and control groups (45% LM; 53% LK). Incontrast, between groups analysis revealed no significant differences in the LM and LK. The treatment group showed a mild superiority in general health improvement compared to that of the control group. Add-on therapy with supplemental zinc sulfate was not associated with significant improvement in patients with chronic rhinosinusitis with nasal polyposis (CRSwNP). The advantage of zinc supplementation on the general health improvement of the patients with CRSwNP requires further assessments.

Introduction

Chronic rhinosinusitis (CRS) is characterized by inflammatory reaction of the membrane of paranasal mucous, particularly by proliferation of inflammatory cells in the lamina propria which causes edema, fibrosis, or epithelial degradation (1, 2). In spite of initiating appropriate treatment, the inflammation lasts for at least four weeks, without an acute episode (3). The symptoms include nasal irritation, rhinorrhea or post nasal discharge, nasal congestion, and blockage and/or facial pain (4, 5). Furthermore, mucosal thickening, polypoid changes, and remarkable eosinophilia occur (3). In case of sever inflammation, nasal polyps infiltrated by inflammatory cells, mainly eosinophils, complicate the issue. Moreover, it forms pseudocysts consisting plasma exudation and albumin retention in the lamina propria (6). Microbial colonization is also found in sinusitis with intense eosinophil-dominated inflammation, nevertheless it remains unclear whether bacterial colonization is the first step prior to inflammation or it is resulted from outflow obstruction caused by polyps (7). Chronic rhinosinusitis (CRS) is one of the most common health care problems responsible for a large number of office visits, which adversely affects the quality of life (8). The exact etiology of CRS is not clear, therefore, there is more difficultly in treatment of the patients with CRS, using a divers class of drugs such as antibiotics, anti-inflammatory drugs, and systemic or topical corticosteroids but the efficacy is controversial (8, 9). Consequently, seeking appropriate treatment to manage the patients with CRS seems to be necessary. A possible option as a treatment supplement could be zinc. Although, there are insufficient evidences to recommend the use of zinc preparations in the patients with CRS, recent researches indicate that zinc supplementation can decrease incidence of many type of infections, vascular endothelial cell activation, oxidative stress, and nuclear factor-kappa B (NF-kB)-DNA binding in mononuclear cells (10-14). Furthermore, it improves T-helper cell function. According to a study in Turkey the serum levels of zinc were lower in the patients with CRS in comparison with the normal population (15). The present study was designed to investigate the impact of zinc supplement as add-on therapy of the patients with CRS especially those with polyposis (CRSwNP).

Experimental

In this single-blind randomized, controlled study, 56 patients with CRSwNP based on the 2012 European position paper on rhinosinusitis and nasal polyps (EPOS 2012) definitions for inclusion criteria for adult, referred to the ear, nose, and throat (ENT) clinic of Loghman Hakim Hospital during 2013 were randomly assigned to the treatment and control groups (16). The study procedure was explained for all patients and an informed written consent was obtained. Moreover, the ethics committee of the Shahid Beheshti University of Medical Sciences approved the study protocol (SBMU.REC.1392.270).

Table 1

Lund-Mackay scoring system for sinus CT scan

Paranasal sinus right sinuses left sinuses
frontal sinus
anterior ethmoidal cells
posterior ethmoidal cells
maxillary sinus
sphenoid sinus
ostiomeatal complex
Total
0 (no abnormality), 1 (partial opacification) or. 2 (complete opacification)
Table 2

Lund-Kennedy scoring system in nasal endoscopy

Feature right nasal cavity left nasal cavity
Polyp (0, 1, 2)
Edema (0, 1, 2)
Discharge (0, 1, 2)
Total
Table 3

Demographic, clinical, and laboratory characteristics of patients in Treatment and control groups

CharacteristicsRoutineTx(n = 16)RoutineTx+Zinc(n = 28)p-value (between groups)
Age42.25 12.4938.21 16.130.393
SexMale10 (62.5%)8 (28.6%)0.028
Female6 (37.5%)20 (71.4%)
ZincBefore93.5 (86-113)89 (87-96)0.377
After108 (78-147)118 (104-149)0.088
p-value (within groups)0.6370.0002
Lund Kennedy endoscopic scoringBefore8.5 (5-12)8 (4-8)0.296
After4 (2-8)4 (2-7)0.591
p-value (within groups)0.0040.002
Non-Inferiority Power100%
Lund MackayCT scoringBefore22.5 (17.5-24)20 (11-23)0.093
After12.5 (11-13)9 (4-23)0.231
p-value (within groups)0.0040.0002
Non-Inferiority Power100%
SNOT20Before56.0 (38-71.5)54 (42-64)0.845
After34.5 (27.5-46.5)33 (24-38)0.144
p-value (within groups)0.0130.00002
Non-Inferiority Power100%
General healthBefore26.5 (23.5-32)26 (23-29)0.555
After23.5 (20.5-24)24 (23-25)0.188
p-value (within groups)0.1080.026
Non-Inferiority Power100%
Comparison of SNOT20 before and after treatment in both groups

Comparison of SNOT20 before and after treatment in both groups

Figure 2

Comparison of SF12 before and after treatment in both groups

Comparison of SF12 before and after treatment in both groups

Figure 3

The trial was submitted in Iranian Registry of Clinical Trial at www.irct.ir and received (IRCT code: IRCT2016092018143N3).

The demographic data including sex, age, and subjective clinical status of patients were obtained based on SNOT20 questionnaire. SNOT20 is a patient-reported measure of outcome in sino-nasal disorders such as rhinosinusitis and nasal polyposis and includes items related to four domains: psychological function, sleep function, rhinological symptoms, and ear and/or facial symptoms (17). The findings of the paranasal CT scan were scored according to Lund-Mackay (LM) scoring system (Table 1) (18). Moreover, the sinonasal endoscopy results were accomplished and were scored based on Lund-Kennedy (LK) scoring system (Table 2) (19).

The first group of the patients (n = 28) received oral dexamethasone for three weeks (with initial dose of 0.02 mg/kg and tapered in 3 weeks), fluticasone 50 mcg spray/2puff/daily, fexophenadine tablet 60 mg daily, montelukast 10 mg daily, plus daily intake of two 220 mg zinc sulfate capsules equivalent to 55 mg elemental zinc, along with nasal irrigation with normal saline 2 times/day. The second group of the patients (control group, n = 28) received the same treatment regimen without zinc sulfate for six weeks (16, 20). The study staff (site investigators and trial coordinating center staff) was unaware of the treatment allocation. At the start of the treatment and at the end of six weeks both groups were compared regarding clinical state based on SNOT20 questionnaire, general health according to patient health questionnaire (SF12) and Lund-Kennedy as well as Lund-Mackay scores. Unfortunately, within the control group 12 (43%) of the patients did not complete the study and were excluded.

All the patients were instructed not to take any supplemental zinc product and also not to change their usual diet during the study period. To confirm medication adherence of the patients, plasma zinc levels were measured at baseline and at the end of the study.

Statistical analysis

Categorical data are presented descriptively as frequency and percentages. Quantitative data with normal distribution (based on Shapiro-Wilk test) are expressed as mean ± SD, and non-normally distributed variables are shown as median and interquartile range (IQR). Data were analyzed by the Statistical Package for the Social Sciences (SPSS), version 20, IBM™. For between-group comparisons the independent samples t-test and the Mann-Whitney U test were used. The paired t-test and the Wilcoxon test were used for within-group comparisons. Furthermore, the Chi-square or the Fisher’s exact tests were employed to compare categorical variables between the study groups. The level of statistical significance was determined at p < 0.05. Moreover, the observed power of non-inferiority tests of comparing mean changes of treatment vs. the control groups were determined by NCSS PASS (Power Analysis and Sample Size), version 11 (21, 22).

Results

In this RCT, 44 patients including 16 patients in routine treatment group ( 10 men and 6 women) and 28 patients in routine plus zinc treatment group (6 men and 20 women) were compared (mean age 39.68 ± 15.06). Figure 1 shows the flowchart of the trial. Difference between treatment and control groups regarding sex and age distribution were not statistically significant (Table 3).There were also no significant difference between baseline Lund scores (endoscopic and CT) of two groups (Table 3). However, the Lund scores decreased significantly after the treatment in the both treatments (55% LM, 50% LK; p < 0.01) and control groups (45% LM, 53% LK; p = 0.004). In the treatment group, serum zinc level significantly increased from median (IQR) 89 (87-96) mcg/dL to 118 (104-149) mcg/dL (p = 0.0002), while it did not dramatically change in the control group (Table 3).

Differences between baseline clinical status, determined by the SNOT20 questionnaire, and baseline general health (SF12), based on the patient health questionnaire, of the two study groups were not significantly regarded. SNOT20 scores were significantly higher in the both treatment (38.89%, p = 0.00002) and control (38.39%, p = 0.013) groups compared to those of the baseline. In the control group, general health status did not change during the study period; however, in the treatment group it showed improvement (Figures 2 and 3).

Discussion

The treatment of CRS is more challenging for both physicians and patients. Traditionally, it is medically treated using systemic antibiotics, topical and systemic corticosteroids, antileukotriene agents, mucolytics, antihistamines, and saline nasal irrigation (23-25). However, previous studies have provided controversial results, and did not introduce an effective drug for CRS treatment (23-25). Therefore, the clinicians have already considered new agents for CRS treatment. In this study, for the first time, we evaluated the possible effect of zinc supplement on CRS. In both of the control and treatment groups, the mean of Lund score (endoscopic and CT) decreased significantly after a six-week treatment. In addition, general health of the patients improved in the Zinc group. Also, after six weeks of treatment, clinical status of the patients in the control and treatment groups improved significantly. Although, the impact of zinc on CRS has not yet been assessed, Unal et al. revealed that the patients with CRS had lower serum zinc levels (15). Another study by Gulani et al. detected decreased serum zinc levels in children with otitis media (26). Similarly, other studies showed zinc increases the immunity system function and decreases the incidence of infective diseases such as diarrhea and other GI infections (27-29). In accordance with these findings, Prasad et al. observed that zinc increases the function of both cellular and humoral immune systems (13). In conclusion, we revealed that addition of zinc supplement was not much effective on treatment of patients with CRSwNP, although, general health status of patients was improved with zinc supplementation.

As a limitation, we could not follow all of the 28 patients in the control group through the 6 weeks study period. This should be acknowledged in the interpretation of our findings. Nevertheless, the high non-inferiority power of this study to find similar effectiveness of zinc supplementation and current therapies for radiologic/endoscopic improvements of CRSwNP patients, in addition to mild superiority of zinc supplementation on general health improvement of the patients is encouraging. Further longitudinal investigations with more powerful designs are recommended.

Acknowledgements

References

  • 1.

    Nasal polyposis and sinusitis.Bachert C, Van Cauwenberge P, editors. . Sanders Publishers; 2003. p. 176-91.

  • 2.

    Moss A, Parsons V. Current estimates from the National Health Interview Survey. United States. 1985 Vital;160:1-182.

  • 3.

    Kaliner MA, Osguthorpe JD, Fireman P, Anon J, Georgitis J, Davis ML, Naclerio R, Kennedy D. Sinusitis: bench to bedside: current findings, future directions. J. Allergy Clin. Immunol. 1997;99:829-48.

  • 4.

    Meltzer EO, Hamilos DL, Hadley JA, Lanza DC, Marple BF, Nicklas RA, Bachert C, Baraniuk J, Baroody FM, Benninger MS, Brook I, Chowdhury BA, Druce HM, Durham S, Ferguson B, Gwaltney JM Jr, Kaliner M, Kennedy DW, Lund V, Naclerio R, Pawankar R, Piccirillo JF, Rohane P, Simon R, Slavin RG, Togias A, Wald ER, Zinreich SJ. Rhinosinusitis: establishing definitions for clinical research and patient care. J. Allergy Clin. Immunol. 2004;114:155-212. [PubMed ID: 15577865].

  • 5.

    Slavin RG, Spector SL, Bernstein IL, Workgroup SU, Kaliner MA, Kennedy DW, Virant FS, Wald ER, Khan DA, Blessing-Moore J. The diagnosis and management of sinusitis: a practice parameter update. J. Allergy Clin. Immunol. 2005;116:13-47.

  • 6.

    Lamblin C, Gosset P, Salez F, Vandezande LM, Perez T, Darras J, Janin A, Tonnel AB, Wallaert B. Eosinophilic airway inflammation in nasal polyposis. J. Allergy Clin. Immunol. 1999;104:85-92. [PubMed ID: 10400844].

  • 7.

    Mygind N, Dahl R, Bachert C. Nasal polyposis, eosinophil dominated inflammation, and allergy. Thorax. 2000;55:79-83.

  • 8.

    Benninger MS, Ferguson BJ, Hadley JA, Hamilos DL, Jacobs M, Kennedy DW, Lanza DC, Marple BF, Osguthorpe JD, Stankiewicz JA. Adult chronic rhinosinusitis: definitions, diagnosis, epidemiology, and pathophysiology. Otolaryngol. Head Neck Surg. 2003;129:1-32. [PubMed ID: 12869908].

  • 9.

    Kern EB, Sherris D, Stergiou AM, Katz LM, Rosenblatt LC, Ponikau J. Diagnosis and treatment of chronic rhinosinusitis: focus on intranasal Amphotericin B. Ther. Clin. Risk Manag. 2007;3:319.

  • 10.

    Sadeghi N, Oveisi MR, Jannat B, Hajimahmoodi M, Behfar A, Behzad M, Norouzi N, Oveisi M, Jannat B. Simultaneous measurement of zinc, copper, lead and cadmium in baby weaning food and powder milk by DPASV. Iran. J. Pharm. Res. 2014;13:345-9. [PubMed ID: 24734090].

  • 11.

    Navaei-Nigjeh M, Gholami M, Fakhri-Bafghi MS, Baeeri M, Abdollahi M. Molecular and biochemical evidences for beneficial effects of zinc oxide nanoparticles in modulation of chlorpyrifos toxicity in human lymphocytes. Iran. J. Pharm. Res. 2018;17:927-39. [PubMed ID: 30127816].

  • 12.

    Bao B, Prasad AS, Beck FW, Snell D, Suneja A, Sarkar FH, Doshi N, Fitzgerald JT, Swerdlow P. Zinc supplementation decreases oxidative stress, incidence of infection, and generation of inflammatory cytokines in sickle cell disease patients. Transl. Res. 2008;152:67-80. [PubMed ID: 18674741].

  • 13.

    Prasad AS, Beck FW, Bao B, Fitzgerald JT, Snell DC, Steinberg JD, Cardozo LJ. Zinc supplementation decreases incidence of infections in the elderly: effect of zinc on generation of cytokines and oxidative stress. Am. J. Clin. Nutr. 2007;85:837-44. [PubMed ID: 17344507].

  • 14.

    Sharma GD, Doershuk CF, Stern RC. Erosion of the wall of the frontal sinus caused by mucopyocele in cystic fibrosis. J. Pediatr. 1994;124:745-7. [PubMed ID: 8176564].

  • 15.

    Ünal M, Tamer L, Pata YS, Kilic S, Degˇirmenci U, Akbaş Y, Görür K, Atik U. Serum levels of antioxidant vitamins, copper, zinc and magnesium in children with chronic rhinosinusitis. J. Trace Elem. Med. Biol. 2004;18:189-92. [PubMed ID: 15646267].

  • 16.

    Fokkens WJ, Lund VJ, Mullol J, Bachert C, Alobid I, Baroody F, Cohen N, Cervin A, Douglas R, Gevaert P, Georgalas C, Goossens H. EPOS 2012: European position paper on rhinosinusitis and nasal polyps. Rhinology. 2012;50:1-12. [PubMed ID: 22469599].

  • 17.

    Jones ML, Piccirillo JF, Haiduk A, Thawley SE. Functional endoscopic sinus surgery: do ratings of appropriateness predict patient outcomes? Am. J. Rhinol. 1998;12:249-55.

  • 18.

    Hopkins C, Browne JP, Slack R, Lund V, Brown P. The Lund-Mackay staging system for chronic rhinosinusitis: how is it used and what does it predict? Otolaryngol. Head Neck Surg. 2007;137:555-61.

  • 19.

    Psaltis AJ, Li G, Vaezeafshar R, Cho KS, Hwang PH. Modification of the lund‐kennedy endoscopic scoring system improves its reliability and correlation with patient‐reported outcome measures. Laryngoscope. 2014;124:2216-23. [PubMed ID: 24615873].

  • 20.

    Yanagisawa H. Zinc deficiency and clinical practice. Japan Med. Assoc. J. 2004;47:359-64.

  • 21.

    Chow SC, Wang H, Shao J. Sample size calculations in clinical research. 1st ed. CRC Press; 2007. p. 237-8.

  • 22.

    Julious SA. Sample sizes for clinical trials with normal data. Stat. med. 2004;23:1921-86. [PubMed ID: 15195324].

  • 23.

    Adelson RT, Adappa ND. What is the proper role of oral antibiotics in the treatment of patients with chronic sinusitis? Curr. Opin. Otolaryngol. Head Neck Surg. 2013;21:61-8.

  • 24.

    Harvey R, Hannan SA, Badia L, Scadding G. Nasal saline irrigations for the symptoms of chronic rhinosinusitis. Cochrane Database Syst. Rev. 2007;2007:183-6.

  • 25.

    Suh JD, Kennedy DW. Treatment options for chronic rhinosinusitis. Proc. Am. Thorac. Soc. 2011;8:132-40. [PubMed ID: 21364231].

  • 26.

    Gulani A, Sachdev HS. Zinc supplements for preventing otitis media. Cochrane Database Syst. Rev. 2012;2012:134-9.

  • 27.

    Lamberti LM, Walker CLF, Chan KY, Jian WY, Black RE. Oral zinc supplementation for the treatment of acute diarrhea in children: a systematic review and meta-analysis. Nutrients. 2013;5:4715-40. [PubMed ID: 24284615].

  • 28.

    Lazzerini M, Ronfani L. Oral zinc for treating diarrhoea in children. Cochrane Database Syst. Rev. 2012;2012:211-5.

  • 29.

    Sazawal S, Black RE, Bhan MK, Bhandari N, Sinha A, Jalla S. Zinc supplementation in young children with acute diarrhea in India. N. Engl. J. Med. 1995;333:839-44. [PubMed ID: 7651474].