Efficacy of rupatadine in reducing the incidence of dengue haemorrhagic fever in patients with acute dengue: A randomised, double blind, placebo-controlled trial.

BACKGROUND: Rupatadine was previously shown to reduce endothelial dysfunction in vitro, reduced vascular leak in dengue mouse models and to reduce the extent of pleural effusions and thrombocytopenia in patients with acute dengue. Therefore, we sought to determine the efficacy of rupatadine in reducing the incidence of dengue haemorrhagic fever (DHF) in patients with acute dengue. METHODS AND FINDINGS: A phase 2, randomised, double blind, placebo controlled clinical trial was carried out in patients with acute dengue in Sri Lanka in an outpatient setting. Patients with ≤3 days since the onset of illness were either recruited to the treatment arm of oral rupatadine 40mg for 5 days (n = 123) or the placebo arm (n = 126). Clinical and laboratory features were measured daily to assess development of DHF and other complications. 12 (9.7%) patients developed DHF in the treatment arm compared to 22 (17.5%) who were on the placebo although this was not significant (p = 0.09, relative risk 0.68, 95% CI 0.41 to 1.08). Rupatadine also significantly reduced (p = 0.01) the proportion of patients with platelet counts <50,000 cells/mm3 and significantly reduced (p = 0.04) persisting vomiting, headache and hepatic tenderness (p<0.0001) in patients. There was a significant difference in the duration of illness (p = 0.0002) although the proportion of individuals who required hospital admission in both treatment arms. Only 2 patients on rupatadine and 3 patients on the placebo developed shock, while bleeding manifestations were seen in 6 patients on rupatadine and 7 patients on the placebo. CONCLUSIONS: Rupatadine appeared to be safe and well tolerated and showed a trend towards a reducing proportion of patients with acute dengue who developed DHF. Its usefulness when used in combination with other treatment modalities should be explored. TRIAL REGISTRATION: International Clinical Trials Registration Platform: SLCTR/2017/024.

Similarities and differences between the 'cytokine storms' in acute dengue and COVID-19.

Severe pneumonia and multiorgan dysfunction in COVID-19 and dengue haemorrhagic fever (DHF) are two diseases that can associate with an altered immune response to the infecting virus. To determine the similarities and differences in the cytokine and chemokine responses in these two infections, we compared responses in patients with varying severity of COVID-19 and acute dengue at different time points of illness. During early disease, patients who proceeded to develop COVID-19 severe pneumonia (SP) and DHF had significantly higher levels of IL-6, IL-10 and MIP3α than those who developed mild illness. The lowest levels of IFNγ in early illness were seen in those who succumbed to their illness due to COVID-19. Levels of serum IL-10 (p = 0.0001), IL-6 (p = 0.002), MIP-3α (p = 0.02) and CD40-L levels (p = 0.002) significantly increased from 5 to 9 day of illness to 10-21 day of illness in patients with moderate-to-severe COVID-19, but not in those with mild illness. In contrast, these cytokine/chemokine levels remained unchanged in those with DHF or dengue fever (DF) during febrile and critical phases. Although IL-10 levels were significantly higher in COVID-19 patients with SP, patients with DHF had 25-fold higher levels, whereas IL-6 levels were 11-fold higher in those with COVID-19 SP. IL-10 and other cytokines were evaluated in a larger cohort of patients during early illness (≤ 4 days) who proceeded to develop DF (n = 71) or DHF (n = 64). Of the cytokines evaluated, IL-10 was significantly higher (p < 0.0001) in those who went on to develop DHF compared to DF. Low IFNγ response to the SARS-CoV2 and high levels of immunosuppressive IL-10 in both COVID-19 and dengue during early illness are indicators of an altered antiviral response potentially contributing to disease severity.