Role of doxycycline in the treatment of dengue infection: An open-label, randomized, controlled, pilot trial

Abstract

Objective: To measure the effect of doxycycline on inflammatory marker [IL-6, TNF-α, ferritin and C reactive protein (CRP)] levels in patients with dengue infection.

Methods: A single-centre, open-label, parallel-group randomized controlled trial was done in PGIMER Chandigarh from June 2021 to October 2022. Patients were randomized using a simple randomization process into two groups: the doxycycline treatment group (n=35) and the control group (n=34). Patients in the treatment group were given oral doxycycline 100 mg twice daily for five days along with standard treatment, whereas patients in the control group received only standard treatment. The objective was to measure the effect of doxycycline on inflammatory markers in dengue infection.

Results: On comparative analysis at day 5, there was a statistically significant reduction in the median values of ferritin and CRP in cases compared to the control group (ferritin: P=0.006 and CRP: P=0.006). No significant reduction was noted in the levels of IL-6 and TNF-α.

Conclusions: Doxycycline treatment led to a reduction of inflammatory markers in dengue infection.

Keywords

Dengue / Cytokine / Doxycycline / Serum ferritin / C reactive protein

References

[1] World Health Organization. Comprehensive guideline for prevention and control of dengue and dengue haemorrhagic fever. 2009. [Online]. Available from: https://www.who.int/publications/i/item/9789241547871. [20 November 2023].

[2] Anderson KB, Gibbons RV, Cummings DA, Nisalak A, Green S, Libraty DH, et al. A shorter time interval between first and second dengue infections is associated with protection from clinical illness in a school-based cohort in Thailand. J Infect Dis 2014; 209(3): 360-368.

[3] Director General of Health Services, Ministry of Health and Family Welfare, Government of India. National guideline for dengue case management during Covid 19 pandemic.2020. [Online]. Available from: https://ncvbdc.mohfw.gov.in/index1. [20 November 2023].

[4] Choudhary S, Kumar D, Bohra GK, Gupta A, Meena DS, Rathore RS, et al. Clinical evaluation of febrile thrombocytopenia in Western Rajasthan-a hospital-based study. Infect Disord Drug Targets 2020; 20(5): 718-723.

[5] Marty AM, Jahrling PB, Geisbert TW. Viral hemorrhagic fevers. Clin Lab Med 2006; 26(2): 345-386.

[6] Castro JEZ, Vado-Solis I, Perez-Osorio C, Fredeking TM. Modulation of cytokine and cytokine receptor/antagonist by treatment with doxycycline and tetracycline in patients with dengue fever. Clin Dev Immunol 2011; 2011: 370872.

[7] Bozza FA, Cruz OG, Zagne SM, Azeredo EL, Nogueira RM, Assis EF, et al. Multiplex cytokine profile from dengue patients: MIP-1beta and IFN-gamma as predictive factors for severity. BMC Infect Dis 2008; 8(1): 1-11.

[8] Bethell DB, Flobbe K, Xuan C, Phuong T, Day NP, Phuong PT, et al. Pathophysiologic and prognostic role of cytokines in dengue hemorrhagic fever. J Infect Dis 1998; 177(3): 778-782.

[9] Hober D, Poli L, Roblin B, Gestas P, Chungue E, Granic G, et al. Serum levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1 β (IL-1β) in dengue-infected patients. Am J Trop Med Hyg 1993; 48(3): 324-331.

[10] Nau R, Tauber S. Immunomodulatory properties of antibiotics. Curr Mol Pharmacol 2008; 1(1): 68-79.

[11] Atrasheuskaya A, Fredeking T, Ignatyev G. Changes in immune parameters and their correction in human cases of tick-borne encephalitis. Clin Exp Immunol 2003; 131(1): 148-154.

[12] Bhattacharjee B, Bhattacharya S, Sardar B, Raj P, Ghosh M, Majumdar D, et al. Dengue and doxycycline-experience in a tertiary care hospital in eastern India in the year 2017-An initial report. J Pharmacol Ther Res 2018; 2: 14-17.

[13] Piper BJ, Alinea AA, Wroblewski JR, Graham SM, Chung DY, McCutcheon LR, et al. A quantitative and narrative evaluation of Goodman and Gilman's pharmacological basis of therapeutics. Pharmacy 2019; 8(1): 1.

[14] Murhekar MV, Kamaraj P, Kumar MS, Khan SA, Allam RR, Barde P, et al. Burden of dengue infection in India, 2017: A cross-sectional population based serosurvey. Lancet Global Health 2019; 7(8): e1065-e1073.

[15] Anker M, Arima Y. Male-female differences in the number of reported incident dengue fever cases in six Asian countries. WPSAR 2011; 2(2): 17.

[16] Vuong NL, Le Duyen HT, Lam PK, Tam DTH, Chau NVV, Kinh NV, et al. C-reactive protein as a potential biomarker for disease progression in dengue: A multi-country observational study. BMC Med 2020; 18(1): 35.

[17] Akash RM, Mubarak R. Correlation between serum ferritin level and severity of dengue fever in a tertiary care center: An observational study. Int J Res Med Sci 2021; 9: 1735-1740.

[18] Lin IF, Lin JN, Tsai CT, Wu YY, Chen YH, Lai CH, et al. Serum C-reactive protein and procalcitonin values in acute Q fever, scrub typhus, and murine typhus. BMC Infect Dis 2020; 20(1): 334.

[19] Al-Kuraishy HM, Al-Gareeb AI, Qusty N, Cruz-Martins N, El-Saber Batiha G. Sequential doxycycline, and colchicine combination therapy in Covid-19: The salutary effects. Pulm Pharmacol Ther 2021; 67: 102008.

[20] Yates PA, Newman SA, Oshry LJ, Glassman RH, Leone AM, Reichel E. Doxycycline treatment of high-risk COVID-19-positive patients with comorbid pulmonary disease. Ther Adv Respir Dis 2020; 14: 1753466620951053.

[21] Choi B, Lee S, Kim SM, Lee EJ, Lee SR, Kim DH, et al. Dipeptidyl peptidase-4 induces aortic valve calcification by inhibiting insulin-like growth factor-1 signaling in valvular interstitial cells. Circulation 2017; 135(20): 1935-1950.

[22] Bajpai G, Verma RK. Role of doxycycline in bleeding manifestations of dengue fever. J Clinical Res and Appl Med 2022; 2(1): 3-6.

[23] Fredeking TM, Zavala-Castro JE, González-Martínez P, Moguel-Rodríguez W, Sanchez EC, Foster MJ. Dengue patients treated with doxycycline showed lower mortality associated to a reduction in IL-6 and TNF levels. Recent Pat Antiinfect Drug Discov 2015; 10(1): 51-58.

[24] Rothan HA, Mohamed Z, Paydar M, Rahman NA, Yusof R. Inhibitory effect of doxycycline against dengue virus replication in vitro. Arch Virol 2014; 159(4): 711-718.

[25] Yang JM, Chen YF, Tu YY, Yen KR, Yang YL. Combinatorial computational approaches to identify tetracycline derivatives as flavivirus inhibitors. PLoS One 2007; 2(5): e428.