# Dengue and Flavivirus Co-Infections: Challenges in Diagnosis, Treatment, and Disease Management
## 4 Severity and Implications of Co-Infections of DENV Serotypes and with Other Flaviviruses
### Co-Infections of DENV with Other Flaviviruses  
The implications of co-exposure and co-transmission of flaviviruses in terms of epidemiology, pathogenesis, and evolution are not fully understood. Limited clinical data and underdiagnosis of flavivirial co-infections add to the poor understanding of flavivirial co-infections in humans and mosquitoes in natural settings. The capacity of _Aedes aegypti_ mosquitoes to harbour and transmit multiple flaviviruses and arboviruses simultaneously has been demonstrated [13]. Moreover, in the long run, flavivirial co-infections may exert a significant influence on the virus evolution, both within the mammalian host and the mosquito vector [13]. In this light, co-infections of flaviviruses are not merely hypothetical; therefore, accurate differential diagnoses for the co-infections, particularly during arboviral outbreaks, are urgently needed [13].  
By far, ZIKV-DENV co-infections are most discussed and documented. Generally, Zika patients are mostly asymptomatic (60-80%), however, milder illnesses, which typically sub-side 4-7 days after the symptom onset, are possibly seen in symptomatic patients [58; 59; 60]. ZIKV-DENV co-infections can result in similar mild symptoms such as fever, headache, joint pain, weakness, conjunctivitis, diarrhoea, nausea, and muscle pain. Serologically, co-infected individuals showed mild thrombocytopenia and leukopenia [20]. Although causing mostly less severe symptoms, fatal cases were reported in adults and foetuses succumbing to ZIKV-DENV co-infections. Most of the casualties had underlying comorbidities. Their histopathological results revealed tubulointerstitial nephritis, acute tubular necrosis, acute motor axonal polyneuropathy, acute demyelinating polyneuropathy, and pneumonia [61]. Discrepancies were, nonetheless, seen in Singapore patients co-infectedby DENV and ZIKV [31]. Besides the typical symptoms, they also showed gastrointestinal sicknesses and atypical rashes. The variations pose challenges to the disease diagnosis and require healthcare professionals to be highly vigilant when assessing patients for possible arboviral infections. This was evident during the Zika outbreak in Singapore, where some patients displayed isolated symptoms [62]. Overall, arboviral infections, particularly dengue, Zika and Chikungunya are known for poor disease prognosis, and patients usually succumb to severe complications due to misdiagnosis or late treatments [58; 59].  
Co-infections of DENV and JEV are also common in Southeast Asia, particularly during the rainy season when _Aedes albopictus_, _Aedes aegypti_ and _Culex tritateniorhynchus_ populations surge significantly [33]. As a neurotrophic virus, JEV primarily impacts the central nervous system (CNS). Likewise, systemic inflammation induced by DENV can also affect the CNS, making the disease diagnosis more complex [63; 64; 65]. The pathogenesis of DENV-JEV co-infection remains unclear, nonetheless, DENV and JEV can enter host cells through shared surface receptors, which might be enhanced by non-neutralizing antibodies, if present, hence more adverse outcomes [66; 67; 68].  
Although less frequently reported, cases involving DENV and SLEV have been documented in endemic areas. For example, [PERSON] et al. [32] reported SLEV and DENV-4 co-infections among Brazilian patients, including a case of triple infection implicating DENV-1, DENV-4, and SLEV. The patients did not exhibit clinical signs and symptoms when the samples were collected, exemplifying the hurdle of early prevention of acute febrile illnesses in those individuals. However, in a co-infection with DENV-3 and SLEV, haemorrhagic symptoms were present but the disease did not exacerbate [69]. The abovementioned scenarios precisely deliberate the complexity and intricacies of flavivirus co-infections, which can be largely influenced by intrinsic and extrinsic factors such as host immune status, viral interference, timing of infections, and environmental conditions [9; 70; 71].