Dengue and SARS-CoV-2 co-circulation and overlapping infections in hospitalized patients

Abstract

Since its emergence in 2019, coronavirus disease (COVID-19) has spread worldwide and consumed public health resources. However, the world still has to address the burdens of other infectious diseases that continue to thrive. Countries in the tropics and neotropics, including Brazil, are affected by annual, cyclic dengue epidemics. Little is known about the impact of subsequent infections between DENV and SARS-CoV-2. Our study was performed on 400 serum samples collected from laboratory-confirmed COVID-19 patients between January and June 2021, months historically known for DENV outbreaks in Brazil. The samples were tested by serology and molecular assays for the presence of DENV and other arboviruses. While no DENV PCR results were detected, 6% were DENV IgM-positive, and 0.25% were DENV NS1-positive according to ELISA. IgM antibodies were isolated by chromatography, and 62.5% of the samples were positive for neutralizing antibodies (FRNT₈₀) against DENV IgM, suggesting a recent infection. We also observed increased IL-10, TNF-α, and IL-1β levels in patients with overlapping SARS-CoV-2/DENV infections. Intriguingly, diabetes was the only relevant comorbidity (p=0.046). High rates of hospitalization (94.9%) and mortality (50%) were found, with a significant increase in invasive mechanical ventilatory support (86.96%) in SARS-CoV-2/DENV- infected patients, suggesting an impact on patient clinical outcomes. When analyzing previous exposure to DENV, secondary dengue patients infected with SARS-CoV-2 more frequently presented with dyspnea and respiratory distress, longer hospital and intensive care unit (ICU) stays (4 and 20.29 days, respectively) and a higher mortality rate (60%). However, a greater proportion of patients with primary DENV infection had fever and cough than patients with secondary dengue (87.50% vs. 33.33%, p=0.027 for fever). Our data demonstrate that differentiating between the two diseases is a great concern for tropical countries and should be explored to improve patient management.

Keywords: SARS-CoV-2; arboviruses; dengue virus; epidemiology; overlapping infection.

Figure 1

Occurrence of dengue, COVID-19, overlapping occurrence, and coinfection with both diseases in Sao Jose do Rio Preto, Sao Paulo, Brazil, from January to July 2021, according to the surveillance system databases. (A) Moving average of notified patients with dengue (red line) and COVID-19 (blue line) and patients with laboratory confirmation for both diseases (green line). (B) Differences in the onsets of symptoms reported in both databases (DENV and COVID-19) and the date of laboratory confirmation of disease. Patients whose first laboratory confirmation was that of dengue are on the red side of the graph. The blue part of the graph represents patients whose first confirmation was that of COVID-19. Only patients with a 30-day difference in laboratory confirmation of overlapping occurrence of both diseases were included in the analysis. (C) Geopolitical map of Brazil and São Paulo state highlighted in gray map of São Paulo state (in gray) indicating the municipality of São José do Rio Preto (SJdRP), located in the Northwest region. (D) Distribution of overlapping infection cases in SJdRP from January to July 2021. (E) Distribution of coinfection-related patient deaths in SJdRP from January to July 2021. All shapefiles used are available at https://portaldemapas.ibge.gov.br.

Figure 2

Geographic and temporal distribution of cases of COVID-19, dengue, and overlapping infection with both diseases identified in the study area of São José do Rio Preto, São Paulo, Brazil, from January to July 2021 by molecular and serologic surveillance. (A) COVID-19-positive patients in SJdRP; (B) dengue-positive patients in SJdRP; (C) COVID-19/dengue infection-positive patients in SJdRP. All shapefiles used are available at https://portaldemapas.ibge.gov.br.

Figure 3

Flowchart of hospital cohort samples. Image created with BioRender.com.

Figure 4

Proinflammatory cytokine profiles of a group of DENV and SARS-CoV-2 infected samples compared with samples positive only for COVID-19. The assay measured the concentrations of (A) IL-1β, (B) IL-6, (C) IL-8, (D) IL-10, and (E) TNF-α in the samples. *p value < 0.05; **p value < 0.01; ***p value < 0.001.