Targeting the pathophysiology of chronic rhinosinusitis with systemic enzyme therapy: a narrative review


  • Amrita Srivastava Department Otorhinolaryngology, Ganesh Shankar Vidyarthi Memorial (GSVM) Medical College, Kanpur, Uttar Pradesh, India
  • Vijay Shukla Department of Otorhinolaryngology, Ajanta Hospital and IVF Centre, Lucknow, Uttar Pradesh, India
  • Gautam V. Daftary Department of Research and Development, Aksigen Hospital Care, Mumbai, Maharashtra, India



Sinusitis, Inflammation, Trypsin, Bromelain, Rutoside


Chronic rhinosinusitis (CRS) is a prevalent condition with significant impact on quality of life and increases the economic burden. Medical treatment modalities for CRS are limited. Most of the drugs, currently in use, target mainly the symptomatology, rather than the pathophysiology of CRS. As more and more information become available, there is better understanding of the underlying mechanisms leading to CRS pathology. This also allows us to identify targets for therapy. The enzyme-flavonoid combination of trypsin-bromelain-rutoside appears to have multiple relevant mechanisms of action to counter some of the known major pathophysiological pathways in CRS. Taken together, the anti-inflammatory, anti-edema, fibrinolytic, vasoprotective and antioxidant actions of the combination can be beneficial in the management of CRS. The literature evidence of these mechanisms, few relevant clinical studies and their potential to benefit CRS therapy has been discussed in this narrative review.


Author Biographies

Amrita Srivastava, Department Otorhinolaryngology, Ganesh Shankar Vidyarthi Memorial (GSVM) Medical College, Kanpur, Uttar Pradesh, India

Associate Professor, Department of Otorhinolaryngology, Ganesh Shankar Vidyarthi Memorial (GSVM) Medical College and Hospital.

Vijay Shukla, Department of Otorhinolaryngology, Ajanta Hospital and IVF Centre, Lucknow, Uttar Pradesh, India

Consultant, Department of Otorhinolaryngology, Ajanta Hospital & IVF Centre.

Gautam V. Daftary, Department of Research and Development, Aksigen Hospital Care, Mumbai, Maharashtra, India

Chairperson, Aksigen Hospital Care Limited.


Mustafa M, Patawari P, Iftikhar H, Shimmi SC, Hussain SS, Sien MM. Acute and chronic rhinosinusitis, pathophysiology and treatment. Int J Pharm Sci Invent. 2015;4(2):30-6.

Chalermwatanachai T, Zhang N, Holtappels G, Bachert C. Association of mucosal organisms with patterns of inflammation in chronic rhinosinusitis. PloS one. 2015;10(8):e0136068.

Ah-See KW, Evans AS. Sinusitis and its management. Bmj. 2007;334(7589):358-61.

Stevens WW, Lee RJ, Schleimer RP, Cohen NA. Chronic rhinosinusitis pathogenesis. J Allergy Clin Immunol. 2015;136(6):1442-53.

Battisti AS, Modi P, Pangia J. Sinusitis. In: StatPearls. StatPearls Publishing, Treasure Island (FL): 2021.

Dar AK, Lone AH. Demographic study of sinusitis in patients visiting Govt. Unani Hospital Srinagar and Ayush Centres in Kashmir. Med J Islamic World Acad Sci. 2013;21(3):115-8.

London NR, Lane AP. Innate immunity and chronic rhinosinusitis: what we have learned from animal models. Laryngoscope Investig Otolaryngol. 2016;1(3):49-56.

Raciborski F, Arcimowicz M, Samoliñski B, Pinkas W, Samel-Kowalik P, Śliwczyñski A. Recorded prevalence of nasal polyps increases with age. Postepy Dermatol Alergol. 2021;38(4):682.

Avdeeva K, Fokkens W. Precision medicine in chronic rhinosinusitis with nasal polyps. Curr Allergy Asthma Rep. 2018;18(4):1-8.

Kashyap GC, Vishwakarma D, Singh SK. Prevalence and Risk Factors of Sinus and Nasal Allergies among Tannery Workers of Kanpur City. Sinusitis. 2021;5(1):5-16.

Ahern S, Cervin A. Inflammation and endotyping in chronic rhinosinusitis-a paradigm shift. Medicina. 2019;55(4):95.

Rosenfeld RM, Piccirillo JF, Chandrasekhar SS, Brook I, Ashok Kumar K, Kramper M, et al. Clinical practice guideline (update): adult sinusitis. Otolaryngol Head Neck Surg. 2015;152(2):S1-39.

Lee S, Lane AP. Chronic rhinosinusitis as a multifactorial inflammatory disorder. Curr Infect Dis Rep. 2011;13(2):159-68.

Laidlaw TM, Buchheit KM. Biologics in chronic rhinosinusitis with nasal polyposis. Ann Allergy Asthma Immunol. 2020;124(4):326-32.

Ambrus JL, Lassman HB, De Marchi JJ. Absorption of exogenous and endogenousproteolytic enzymes. Clin Pharmacol Ther. 1967;8(3):362-8.

Innerfield I, Schwarz A, Angrist A. Intravenous trypsin: Its anticoagulant, fibrinolytic and thrombolytic effects. J Clin Invest. 1952;31:1049-55.

Walad M, Honzikova M, Lysikova M. Systemic enzyme support: an overview. Nutr News. 2008;4:2-5.

Alexander B, Pechet L, Kliman A. Proteolysis, fibrinolysis, and coagulation: Significance in thrombolytic therapy. Circulation. 1962;26:596-611.

Lehmann PV. Immunomodulation by proteolytic enzymes. Nephrol Dial Transplant. 1996;11:952-5.

Targoni O, Lehmann PV. Modulation of the activation threshold for autoreactive T cells via systemic enzyme therapy with phlogenzym®. J Neuroimmunol. 1995;56:66.

White MJ, Gomer RH. Trypsin, tryptase, and thrombin polarize macrophages towards a pro-fibrotic M2a phenotype. PLoS One. 2015;10:e0138748

Fitzhugh DJ, Shan S, Dewhirst MW, Hale LP. Bromelain treatment decreases neutrophil migration to sites of inflammation. Clin Immunol. 2008;128(1):66-74.

Lotz-Winter H. On the pharmacology of bromelain: an update with special regard to animal studies on dose-dependent effects. Planta Medica. 1990;56(03):249-53.

Pavan R, Jain S, Kumar A. Properties and therapeutic application of bromelain: a review. Biotechnol Res Int. 2012;2012.

Mynott TL, Ladhams A, Scarmato P, Engwerda CR. Bromelain, from pineapple stems, proteolytically blocks activation of extracellular regulated kinase-2 in T cells. J Immunol. 1999;163(5):2568-75.

Müller S, März R, Schmolz M, Drewelow B, Eschmann K, Meiser P. Placebo‐controlled randomized clinical trial on the immunomodulating activities of low‐and high‐dose bromelain after oral administration-new evidence on the antiinflammatory mode of action of bromelain. Phytother Res. 2013;27(2):199-204.

Hale LP, Greer PK, Sempowski GD. Bromelain treatment alters leukocyte expression of cell surface molecules involved in cellular adhesion and activation. Clin Immunol. 2002;104:183-90.

Oh-ishi S, Uchida Y, Ueno A, Katori M. Bromelain, a thilprotease from pineapple stem, depletes high molecular weight kininogen by activation of Hageman factor (factor XII). Thromb Res. 1979;14:665-72.

Suda H, Yamauchi H, Iso T. Potentiative effect of angiotensin converting enzyme inhibitor on carrageenan edema in rats and the role of tissue kininogen. J Pharmacobiodyn. 1984;7:372-7.

Sarmento DM, Moura DP, Lopes SL, Silva SC. Bromelain monograph. Altern Med Rev. 2010;15:361-8.

Metzig CA, Grabowska ED, Eckert KL, Rehse KL, Maurer HR. Bromelain proteases reduce human platelet aggregation in vitro, adhesion to bovine endothelial cells and thrombus formation in rat vessels in vivo. In Vivo. 1999;13:7-12.

Gaspani L, Limiroli E, Ferrario P, Bianchi M. in vivo and in vitro effects of bromelain on PGE2 and SP concentrations in the inflammatory exudate in rats. Pharmacology. 2002;65:83-6.

Sahbaz A, Aynioglu O, Isik H, Ozmen U, Cengil O, Gun BD, et al. Bromelain: a natural proteolytic for intra-abdominal adhesion prevention. Int J Surg. 2015;14:7-11.

Maurer HR. Bromelain: biochemistry, pharmacology and medical use. Cell Mol Life Sci. 2001;58(9):1234-45.

Sun CL, Wei J, Bi LQ. Rutin attenuates oxidative stress and proinflammatory cytokine level in adjuvant induced rheumatoid arthritis via inhibition of NF-κB. Pharmacology. 2017;100(1-2):40-9.

Gul A, Kunwar B, Mazhar M, Faizi S, Ahmed D, Shah MR, et al. Rutin and rutin-conjugated gold nanoparticles ameliorate collagen-induced arthritis in rats through inhibition of NF-κB and iNOS activation. Int. Immunopharmacol. 2018;59:310-7.

Liu S, Adewole D, Yu L, Sid V, Wang B, Karmin O, et al. Rutin attenuates inflammatory responses induced by lipopolysaccharide in an in vitro mouse muscle cell (C2C12) model. Poult Sci. 2019;98:2756-64

Kauss T, Moynet D, Rambert J, Al-Kharrat A, Brajot S, Thiolat D, et al. Rutoside decreases human macrophage-derived inflammatory mediators and improves clinical signs in adjuvant-induced arthritis. Arthritis Res Ther. 2008;10(1):1-9.

Ma JQ, Liu CM, Yang W. Protective effect of rutin against carbon tetrachloride-induced oxidative stress, inflammation and apoptosis in mouse kidney associated with the ceramide, MAPKs, p53 and calpain activities. Chem Biol Interact. 2018;286:26-33.

Afanas' ev IB, Dcrozhko AI, Brodskii AV, Kostyuk VA, Potapovitch AI. Chelating and free radical scavenging mechanisms of inhibitory action of rutin and quercetin in lipid peroxidation. Biochem Pharmacol. 1989;38:1763-9.

Khajevand-Khazaei MR, Mohseni-Moghaddam P, Hosseini M, Gholami L, Baluchnejadmojarad T, Roghani M. Rutin, a quercetin glycoside, alleviates acute endotoxemic kidney injury in C57BL/6 mice via suppression of inflammation and up-regulation of antioxidants and SIRT1. Eur J Pharmacol. 2018;833:307-13.

Gong G, Qin Y, Huang W, Zhou S, Yang X, Li D. Rutin inhibits hydrogen peroxide-induced apoptosis through regulating reactive oxygen species mediated mitochondrial dysfunction pathway in human umbilical vein endothelial cells. Eur J Pharmacol. 2010;628:27-35.

Gerdin B, Svensjö E. Inhibitory effect of the flavonoid O-(beta-hydroxyethyl)-rutoside on increased microvascular permeability induced by various agents in rat skin. Int J Microcirc Clin Exp. 1983;2:39-46.

Blumberg S, Clough G, Michel C. Effects of hydroxyethyl rutosides upon the permeability of single capillaries in the frog mesentery. Br J Pharmacol. 1989;96:913-9.

Sheu JR, Hsiao G, Chou PH, Shen MY, Chou DS. Mechanisms involved in the antiplatelet activity of rutin, a glycoside of the flavonol quercetin, in human platelets. J Agric Food Chem. 2004;52:4414-8.

Chen WM, Jin M, Wu W. Experimental study on inhibitory effect of rutin against platelet activation induced by platelet activating factor in rabbits. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2002;22:283-5.

Taub, SJ. Use of bromelains in sinusitis: A double-blind clinical evaluation. Eye Ear Nose Throat Mon. 1967;46(3):361-2.

Ryan RE. A double-blind clinical evaluation of bromelain in the treatment of acute sinusitis. Headache. 1967;7:13-6.

Seltzer, AP. Adjunctive use of bromelains in sinusitis: A controlled Study. Eye Ear Nose Throat Mon. 1967;46(10):1281-8.

Wohlrab R. Enzymkombinationspräparat zur therapie der sinusitis acuta. Der Allgemeinarzt. 1993;15:104-14.

Braun JM, Schneider B, Beuth HJ. Therapeutic use, efficiency and safety of the proteolytic pineapple enzyme Bromelain-POS® in children with acute sinusitis in Germany. In Vivo. 2005;19(2):417-21.

Buttner L, Achilles N, Bohm M, Shah-Hosseini K, Mosges R. Efficacy and tolerability of bromelain in patients with chronic rhinosinusitis--a pilot study. B-ENT. 2013;9(3):217-25.

Clarsund M, Fornbacke M, Uller L, Johnston SL, Emanuelsson CA. A randomized, double-blind, placebo-controlled pilot clinical study on ColdZyme® Mouth Spray against rhinovirus-induced common cold. Open J Respir Dis. 2017;7(4):125-35.

Turner RB, Fowler SL, Berg K. Treatment of the common cold with troxerutin. APMIS. 2004;112(9):605-11.

Yao J, Zhang Y, Wang XZ, Zhao J, Yang ZJ, Lin YP, et al. Flavonoids for treating viral acute respiratory tract infections: a systematic review and meta-analysis of 30 randomized controlled trials. Front Public Health. 2022;10.






Review Articles