Clinical manifestations of dengue in relation to dengue serotype and genotype in Malaysia: A retrospective observational study

Background Malaysia experienced an unprecedented dengue outbreak from the year 2014 to 2016 that resulted in an enormous increase in the number of cases and mortality as compared to previous years. The causes that attribute to a dengue outbreak can be multifactorial. Viral factors, such as dengue serotype and genotype, are the components of interest in this study. Although only a small number of studies investigated the association between the serotype of dengue virus and clinical manifestations, none of these studies included analyses on dengue genotypes. The present study aims to investigate dengue serotype and genotype-specific clinical characteristics among dengue fever and severe dengue cases from two Malaysian tertiary hospitals between 2014 and mid-2017. Methodology and principal findings A total of 120 retrospective dengue serum specimens were subjected to serotyping and genotyping by Taqman Real-Time RT-PCR, sequencing and phylogenetic analysis. Subsequently, the dengue serotype and genotype data were statistically analyzed for 101 of 120 corresponding patients’ clinical manifestations to generate a descriptive relation between the genetic components and clinical outcomes of dengue infected patients. During the study period, predominant dengue serotype and genotype were found to be DENV 1 genotype I. Additionally, non-severe clinical manifestations were commonly observed in patients infected with DENV 1 and DENV 3. Meanwhile, patients with DENV 2 infection showed significant warning signs and developed severe dengue (p = 0.007). Cases infected with DENV 2 were also commonly presented with persistent vomiting (p = 0.010), epigastric pain (p = 0.018), plasma leakage (p = 0.004) and shock (p = 0.038). Moreover, myalgia and arthralgia were highly prevalent among DENV 3 infection (p = 0.015; p = 0.014). The comparison of genotype-specific clinical manifestations showed that DENV 2 Cosmopolitan was significantly common among severe dengue patients. An association was also found between genotype I of DENV 3 and myalgia. In a similar vein, genotype III of DENV 3 was significantly common among patients with arthralgia. Conclusion The current data contended that different dengue serotype and genotype had caused distinct clinical characteristics in infected patients.
Author summary The study highlights interesting relationship between viral factors and clinical manifestation of dengue disease during an outbreak. The viral factors which include serotype and genotype of dengue virus were studied to discover if the clinical manifestation in patients were serotype and genotype-specific. As most clinical symptoms of severe dengue infection only manifest at a much later stage of dengue infection, therefore, information on serotype or genotype-specific dengue manifestations may serve as early surrogate markers to predict disease progression. We found that specific clinical manifestations were over-represented by a specific DENV serotype and genotype. Severe dengue was significantly present in DENV 2 Cosmopolitan-infected group while non-severe dengue was prominent among DENV 1 genotype I-infected patients. DENV 3-infected patients commonly manifested musculoskeletal symptoms. This study was undertaken between 2014 and mid-2017, which was considered to be crucial, given that Malaysia experienced an unprecedented outbreak of dengue during this period. Consequently, the occurrence of serotype shift and possible re-emergence of DENV 3 genotype I were reported.