Impact of dengue virus (DENV) co-infection on clinical manifestations, disease severity and laboratory parameters

Abstract

BackgroundThe co-circulation of 4 DENV serotypes in geographically expanding area, has resulted in increasing occurrence of DENV co-infections. However, studies assessing the clinical impact of DENV co-infections have been scarce and have involved small number of patients. This study explores the impact of DENV co-infection on clinical manifestations and laboratory parameters.MethodsThis retrospective study involved consecutive hospitalized patients with non-structural protein 1 (NS1) antigen positivity during an outbreak (Jan to April 2014). Multiplex RT-PCR was performed directly on NS1 positive serum samples to detect and determine the DENV serotypes. All PCR-positive serum samples were inoculated onto C6/36 cells. Multiplex PCR was repeated on the supernatant of the first blind passage of the serum-infected cells. Random samples of supernatant from the first passage of C6/36 infected cells were subjected to whole genome sequencing. Clinical and laboratory variables were compared between patients with and without DENV co-infections.ResultsOf the 290 NS1 positive serum samples, 280 were PCR positive for DENV. Medical notes of 262 patients were available for analysis. All 4 DENV serotypes were identified. Of the 262 patients, forty patients (15.3 %) had DENV co-infections: DENV-1/DENV-2(85 %), DENV-1/DENV-3 (12.5 %) and DENV-2/DENV-3 (2.5 %). Another 222 patients (84.7 %) were infected with single DENV serotype (mono-infection), with DENV- 1 (76.6 %) and DENV- 2 (19.8 %) predominating. Secondary dengue infections occurred in 31.3 % patients. Whole genome sequences of random samples representing DENV-1 and DENV-2 showed heterogeneity amongst the DENVs.Multivariate analysis revealed that pleural effusion and the presence of warning signs were significantly higher in the co-infected group, both in the overall and subgroup analysis. Diarrhoea was negatively associated with co-infection. Additionally, DENV-2 co-infected patients had higher frequency of patients with severe thrombocytopenia (platelet count < 50,000/mm3), whereas DENV-2 mono-infections presented more commonly with myalgia. Elevated creatinine levels were more frequent amongst the co-infected patients in univariate analysis. Haemoconcentration and haemorrhagic manifestations were not higher amongst the co-infected patients. Serotypes associated with severe dengue were: DENV-1 (n = 9), DENV-2 (n = 1), DENV-3 (n = 1) in mono-infected patients and DENV-1/DENV-2 (n = 5) and DENV-1/DENV-3 (n = 1) amongst the co-infected patients.ConclusionDENV co-infections are not uncommon in a hyperendemic region and co-infected patients are skewed towards more severe clinical manifestations compared to mono-infected patients.

An epidemiological study of dengue and its coinfections in Delhi

“…This is the first such report from Delhi, although all the four serotypes were found in two patients from Kerala in year 2013 (Reddy et al, 2017). Dengue patients infected with multiple serotypes of DENV are more prone to have severe manifestations than with mono infection (Dhanoa et al, 2016). Further, severe clinical manifestations are commonly seen with DENV -2, hemorrhagic manifestations with DENV-4, liver involvement with DENV-3; while DENV-1 usually has mild clinical presentation (Kumaria, 2010;Kalayanarooj and Nimmannitya, 2000).…”

Etiologies of Acute Undifferentiated Febrile Illness in Bangkok, Thailand

“…1,35 Furthermore, concurrent infection with two serotypes of dengue found in six cases in our report is occasionally reported in hyperendemic areas, especially during outbreaks. 36,37 However, there were limited data about the characteristic of cases and pathogenesis. It would be interesting to explore further on the study in both epidemiological data and pathogenesis.…”

Dengue virus surveillance: circulation of DENV-1, DENV-2, DENV-3 and DENV-4 in mosquitoes around Taman Connaught, Cheras

“…However, there has yet to be a clear correlation between the dominant DENV serotype found in infected humans and the dominant DENV serotype within mosquitoes, as infection dynamics depend on the number of infected mosquitoes, proximity to humans, weather patterns, virological factors and other elements (Bar-Zeev et al, 1977;Cogan, 2019) Co-infections are associated with more severe clinical manifestations of the disease, most notably with increased likelihood of developing Dengue Hemorrhagic Fever (DHF) (Gubler, 1998). The circulation of multiple DENV serotypes in mosquito vectors may increase both the occurrence of co-infection within humans and also the risk of subsequent secondary infection with a different dengue serotypes, leading to poorer prognoses (Dhanoa et al, 2016). DENV-2 + DENV-3 co-infections in individual mosquitoes (10 mosquitoes with DENV-2 + DENV-3 of 15 total co-infections) were previously reported in Selangor (Lau et al, 2015).…”

“…In a 2016 study conducted in Johor Bahru (Malaysia) using 262 Dengue positive patient sera samples, 40 (15%) of samples were identified as co-infections (with DENV-1/DENV-2 contributing 85% of co-infections) (Dhanoa et al, 2016). The prevalence of several serotypes within a community or region collectively increases the impact of seasonal dengue outbreaks and coinfections and monitoring of dengue virus within the mosquito population and subsequent control measures may prove to be a vital precautionary step and serve as an early warning system to thwart the increasing burden of dengue outbreaks.…”