Inflammatory Sequelae After Chikungunya Virus Infection
Pedro A Adrover-López, MD
Michael J Gonzalez, NMD, DSc, PhD, FACN
Jorge R Miranda-Massari, Pharm D
Jorge Duconge, PhD
Miguel J Berdiel, MD


Omega-3 fatty acids
Vitamin C


Patients infected with chikungunya virus (CHIKV) exhibit specific characteristics, including high fever, rigors, headache, photophobia, petechial rash or maculopapular rash, and incapacitating joint pain. It is thought that the presence of CHIKV immunoglobulin M (IgM) and IgG antibodies play an important role in a new type of rheumatoid arthritis reported in 2009. It has been reported that 97% of patients with CHIKV infection complain of recurrent symptoms for 6 months. Fatigue was considered to be totally disabling in 4.6% of patients and very disabling in 42.8% of patients. Only 10% of patients considered their mood normal, whereas 37.8% felt demoralized and 43.9% considered their mood weakened. This article presents our review of the literature in which we looked for an effective nutritional approach for the treatment of CHIKV infection and its sequelae. It has been reported that the use of omega-3 fatty acids, intravenous vitamin C, bromelain, and curcumin plays an important role in decreasing the inflammatory response during an acute viral illness and other inflammatory processes, such as rheumatoid arthritis. Our general recommendation based on the current evidence, is that the use of omega-3 fatty acids, intravenous vitamin C, bromelain, and curcumin could be an effective treatment option for the inflammatory sequelae of CHIKV infection.



Schuffenecker I, Iteman I, Michault A, et al. Genome microevolution of chikungunya viruses causing the Indian Ocean outbreak. PLoS Med. 2006; 3:e263.
Chevillon C, Briant L, Renaud F, Devaux C. The Chikungunya threat: an ecological and evolutionary perspective. Trends Microbiol. 2008; 16:80–8.
Diallo M, Thonnon J, Traore-Lamizana M, Fontenille D. Vectors of Chikungunya virus in Senegal: current data and transmission cycles. Am J Trop Med Hyg. 1999; 60:281–6.
Simon F, Parola P, Grandadam M, et al. Chikungunya infection: an emerging rheumatism among travelers returned from Indian Ocean islands: report of 47 cases. Medicine (Baltimore). 2007; 86:123–37.
Sissoko D, Malvy D, Ezzedine K, et al. Post-epidemic Chikungunya disease on Reunion Island: course of rheumatic manifestations and associated factors over a 15-month period. PLoS Negl Trop Dis. 2009; 3:e389.
Hoarau JJ, Jaffar Bandjee MC, Krejbich Trotot P, et al. Persistent chronic inflammation and infection by Chikungunya arthritogenic alphavirus in spite of a robust host immune response. J Immunol. 2010; 184:5914–27.
Simon F, Javelle E, Oliver M, et al. Chikungunya virus infection. Curr Infect Dis Rep. 2011; 13:218–28.
Queyriaux B, Simon F, Grandadam M, et al. Clinical burden of chikungunya virus infection. Lancet Infect Dis. 2008; 8:2–3.
Bouquillard E, Combe B. A report of 21 cases of rheumatoid arthritis following Chikungunya fever: a mean follow-up of 2 years. Joint Bone Spine. 2009; 76:654–7.
Ozden S, Huerre M, Riviere JP, et al. Human muscle satellite cells as targets of Chikungunya virus. PLoS One. 2007; 2:e527.
Lidbury BA, Rulli NE, Suhrbier A, et al. Macrophage-derived proinflammatory factors contribute to the development of arthritis and myositis after infection with an arthrogenic alphavirus. J Infect Dis. 2008; 197:1585–93.
Malvy D, Ezzedine K, Mamani-Matsuda M, et al. Destructive arthritis in a patient with chikungunya virus infection with persistent specific IgM antibodies. BMC Infect Dis. 2009; 9:200.
Rot A, von Andrian UH. Chemokines in innate and adaptive host defense: basic chemokinese grammar for immune cells. Annu Rev Immunol. 2004; 22:891–928.
Dinarello CA. Biologic basis for interleukin-1 in disease. Blood. 1996; 87:2095–147.
Miossec P, Korn T, Kuchroo VK. Interleukin-17 type 17 helper T cells. N Engl J Med. 2009; 361:888–98.
Chow A, Her Z, Ong EKS, et al. Persistent arthralgia induced by chikungunya virus infection is associated with interleukin-6 and granulocyte macrophage colony-stimulating factor. J Infect Dis. 2011; 203:149–57.
Hegab A, Kubo H, Yamaya M, et al. Intranasal HGF administration ameliorates the physiologic morphologic changes in lung emphysema. Mol Ther. 2008; 16:1417–26.
Lee TH, Hoover RL, Williams JD, et al. Effects of dietary enrichment with eicosapentaenoic acid and docosahexaenoic acid on in vitro neutrophil and monocyte leukotriene generation and neutrophil function. N Engl J Med. 1985; 312:1217–24.
Endres S, Ghorbani R, Kelley VE, et al. The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells. N Engl J Med. 1989; 320:265–71.
Schmidt EB, Pedersen JO, Varming K, et al. n-3 fatty acids and leukocyte chemotaxis: effects in hyperlipidemia, and dose-response studies in healthy males. Arterioscler Thromb. 1991; 11:429–35.
Tull SP, Yates CM, Maskrey BH, et al. Omega-3 fatty acids and inflammation: novel interactions reveal a new step in neutrophil recruitment. PLoS Biol. 2009; 7:e1000177.
Yates CM, Tull SP, Madden J, et al. Docosahexaenoic acid inhibits the adhesion of flowing neutrophils to cytokine stimulated human umbilical vein endothelial cells. J Nutr. 2011; 141:1331–4.
Hughes DA, Pinder AC, Piper Z, et al. Fish oil supplementation inhibits the expression of major histocompatibility complex class II molecules and adhesion molecules on human monocytes. Am J Clin Nutr. 1996; 63:267–72.
Luu NT, Madden J, Calder PC, et al. Comparison of the pro-inflammatory potential of monocytes from healthy adults and those with peripheral arterial disease using an in vitro culture model. Atherosclerosis. 2007; 193:259–68.
De Catherina R, Cybulsky MI, Clinton SK, et al. The omega-3 fatty acid docosahexaenoate reduces cytokine-induced expression of proatherogenic and proinflammatory proteins in human endothelial cells. Arterioscler Thromb. 1994; 14:1829–36.
Khalfoun B, Thibault F, Watier H, et al. Docosahexaenoic and eicosapentaenoic acids inhibit in vitro human endothelial cell production of interleukin-6. Adv Exp Med Biol. 1997; 400B:589–97.
Novak TE, Babcock TA, Jho DH, et al. NF-κB inhibition by ω-3 fatty acids modulates LPS-stimulated macrophage TNF-α transcription. Am J Physiol Lung Cell Mol Physiol. 2003; 284:L84–9.
Kremeret JM, Lawrence DA, Jubiz W, et al. Dietary fish oil and olive oil supplementation in patients with rheumatoid arthritis. Arthritis Rheumatol. 1990; 33:810–20.
Esperson GT, Grunnet N, Lervang HH, et al. Decreased interleukin-1β levels in plasma from rheumatoid arthritis patients after delivery supplementation with n-3 polyunsaturated fatty acids. J Clin Rheumatol. 1992; 11:393–5.
Kolahi S, Ghorbanihaghjo A, Alizadeh S, et al. Fish oil supplementation decreases serum soluble receptor activator of nuclear factor-κB ligand/osteoprotegerin ratio in female patients with rheumatoid arthritis. J Clin Biochem. 2010; 43:576–80.
Szanto A, Nagy L. The many faces of PPARγ: anti-inflammatory by any means? Immunobiology. 2008; 213:789–803.
Forman BM, Chen J, Evans RM. Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors α and δ. Proc Natl Acad Sci USA. 1997; 94:4312–7.
Kong W, Yeng JH, Vassiliou E, et al. Docosahexaenoic acid prevents dendritic cell maturation and in vitro and in vivo expression of the IL-12 cytokine family. Lipids Health Dis. 2010; 9:12.
Chapkin RS, Akoh CC, Miller CC. Influence of dietary n-3 fatty acids on macrophage glycerophospholipid molecular species and peptidoleukotriene synthesis. J Lipid Res. 1991; 32:1205–13.
Yaqoob P, Calder P. Effects of dietary lipid manipulation upon inflammatory mediator production by murine macrophages. Cell Immunol. 1995; 163:120–8.
Peterson LD, Jeffery NM, Thies F, et al. Eicosapentaenoic and docosahexaenoic acids alter rat spleen leukocyte fatty acid composition and prostaglandin E2 production but have different functions and cell-mediated immunity. Lipids. 1998; 33:171–80.
Trebble TM, Wootton SA, Miles EA, et al. Prostaglandin E2 production and T-cell function after fish-oil supplementation: response to antioxidant co-supplementation. Am J Clin Nutr. 2003; 78:376–82.
Rees D, Miles EA, Banerjee T, et al. Dose-related effects of eicosapentaenoic acid on innate immune function in healthy humans: a comparison of young and older men. Am J Clin Nutr. 2006; 83:331–42.
Calder PC. Omega-3 polyunsaturated fatty acids and inflammatory processes: nutrition or pharmacology? Br J Clin Pharmacol. 2013; 75:645–62.
Bowie AG, O’Neill LAJ. Vitamin C inhibits NF-κB activation by TNF via the activation of p38 mitogen-activated protein kinase. J Immunol. 2000; 165:7180–8.
Mikirova N, Casciari J, Rogers A, Taylor P. Effect of high-dose intravenous vitamin C on inflammation in cancer patients. J Transl Med. 2012; 10:189.
Padayatty SJ, Sun AY, Chen Q, et al. Vitamin C: intravenous use by complementary and alternative medicine practitioners and adverse effects. PLoS One. 2010; 5:e11414.
Byun SH, Jeon Y. Administration of vitamin C in a patient with herpes zoster – a case report. Korean J Pain. 2011; 24:108–11.
Harakek S, Jariwalla R, Pauling L. Suppression of human immunodeficiency virus replication by ascorbate in chronically and acutely infected cells. Proc Natl Acad Sci USA. 1990; 87:7245–9.
Gonzalez M, Miranda-Massari JR, Berdiel MJ, et al. High dose intravenous vitamin C and Chikungunya fever: a case report. J Orthomol Med. 2014; 29:154–6.
Maurer HR. Bromelain: biochemistry, pharmacology and medical use. Cell Mol Life Sci. 2001; 58:1234–45.
Taussig SJ, Batkin S. Bromelain, the enzyme complex of pineapple (Ananas comosus) and its clinical application: an update. J Ethnopharmacol. 1988; 22:191–203.
Rovenská E, Svík K, Stancíková M, et al. Enzyme and combination therapy with cyclosporin A in the rat developing adjuvant arthritis. Int J Tissue React. 1999; 21:105–11.
Rovenská E, Svík K, Stancíková M, Rovenský J. Inhibitory effect of enzyme therapy and combination therapy with cyclosporin A on collagen-induced arthritis. Clin Exp Rheumatol. 2001; 19:303–9.
Wittenborg A, Bock PP, Harnish J, et al. Comparative epidemiological study in patients with rheumatic diseases illustrated in an example of a treatment with non-steroidal anti-inflammatory drugs versus oral enzyme combination preparation [in German]. Arzneimittelforschung. 2000; 50:728–38.
Akhtar NM, Naseer R, Farooqi AZ, et al. Oral enzyme combination versus diclofenac in the treatment of osteoarthritis of the knee – a double-blind prospective randomized study. Clin Rheumatol. 2004; 23:410–5.
Majima M, Nishiyama K, Iguchi Y, et al. Determination of bradykinin-(1–5) in inflammatory exudate by a new ELISA as a reliable indicator of bradykinin generation. Inflamm Res. 1996; 45:416–23.
Ogino M, Majima M, Kawamura M, et al. Increased migration of neutrophils to granulocyte-colony stimulating factor in rat carrageenin-induced pleurisy: roles of complement, bradykinin, and inducible cyclooxygenase-2. Inflamm Res. 1996; 45:335–46.
Fitzhugh DJ, Shan S, Dewhirst MW, et al. Bromelain treatment decreases neutrophil migration to sites of inflammation. Clin Immunol. 2008; 128:66–74.
Aggarwal BB, Sung B. Pharmacological basis for the role of curcumin in chronic diseases: an age-old spice with modern targets. Trends Pharmacol Sci. 2008; 30:85–94.
Zhang F, Altorki NK, Mestre JR, et al. Curcumin inhibits cyclooxygenase-2 transcription in bile acid and phorbol ester treated human gastrointestinal epithelial cells. Carcinogenesis. 1999; 20:445–51.
Huang MT, Lysz T, Ferraro T, et al. Inhibitory effects of curcumin on in vitro lipoxygenase and cyclooxygenase activities in mouse epidermis. Cancer Res. 1991; 51:813–9.
Gafner S, Lee SK, Cuendet M, et al. Biologic evaluation of curcumin and structural derivatives in cancer chemoprevention model systems. Phytochemistry. 2004; 65:2849–59.
Koeberle A, Northoff H, Werz O. Curcumin blocks prostaglandin E2 biosynthesis through direct inhibition of the microsomal prostaglandin E2 synthase-1. Mol Cancer Ther. 2009; 8:2348–55.
Banji D, Pinnapureddy J, Banji OJ, et al. Synergistic activity of curcumin with methotrexate in ameliorating Freund’s complete adjuvant induced arthritis with reduced hepatotoxicity in experimental animals. Eur J Pharmacol. 2011; 668:293–8.
Belcaro G, Cesarone MR, Dugall M. et al. Product-evaluation registry of Meriva®, a curcumin-phosphatidylcholine complex, for the complementary management of osteoarthritis. Panminerva Med. 2010; 52(2 Suppl 1):55–62.
Chandran B, Goel A. A randomized, pilot study to assess the efficacy and safety of curcumin in patients with active rheumatoid arthritis. Phytother Res. 2012; 26:1719–25.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY-NC-ND 4.0). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.