# 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 Serotypes  
Although all DENV serotypes share a similar infection mechanism, previous findings indicated that some genotypes are more virulent within a particular serotype, leading to a higher likelihood of severe symptoms. This results in a spectrum of disease severity in the affected population [45]. A co-infection of DENV-1 with DENV-2 is associated with a higher frequency of severe thrombocytopenia on admission and lower nadir platelet counts than mono-infected patients [19]. In turn, warning signs and severe disease manifestations are expectedly elevated in co-infected individuals, such as higher risks for developing pleural effusion and at least one severe dengue manifestation. However, some findings reported otherwise where the overall disease severity among co-infected patients was mild, with only a few severe cases without fatality [19; 46; 47]. In light of the discrepancies, in 2012, WHO broadened the scope of classic dengue fever and introduced the term \"expanded \begin{table}
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**Category** & **Specific Aspect** & **Summary** & **References** &
\begin{tabular}{c} **Evidence** \\ **Strengths/Controversies** \\ \end{tabular} \\ \hline
4. Immunological interactions and diagnosis & Antibody cross-reactivity & Due to \(\sim\)60\% nucleotide similarity between DENV and ZIKV. & [26; 27; 28] & Well established in serology analyses; significant implications in clinical management. \\ \hline  & Antibody-dependent enhancement (ADE) & Cross-reactive, non-neutralizing antibodies may enhance viral entry, worsening disease severity. Impacts on vaccine development. & [29; 30; 31] & Strong theoretical and experimental evidence. \\ \hline  & Diagnostic limitations & Overlapping clinical symptoms lead to frequent misdiagnosis. The current WHO guidelines may miss out on co-infection cases. & [34; 35; 36; 37] & Widely acknowledged limitations; highlights urgent need for differential diagnostic tools. \\ \hline \hline \end{tabular}
\end{table} 
Table 2: _Cont._-dengue syndrome\". Expanded dengue syndrome can be applied to co-infections as it regularly involves multiple vital organs and leads to severe shock [48; 49]. Similar to DENV mono-infections, the severity of co-infections can also be divided into mild and severe clinical presentations [3]. For mild cases, a few studies reported that patients concurrently infected with dengue serotypes recovered without relapse. They initially presented with typical dengue symptoms such as high fever, headache, arthalgia, myalgia, retro-orbital pain, and asthenia, but without any haemorrhagic manifestations [50; 51; 52]. Upon admission, they demonstrated mildly elevated transaminase levels, a common marker for liver inflammation or damage. More interestingly, most of them experienced primary infections [50; 53]. In dengue, progression of the disease into severe forms may be influenced by non-viral factors such as the host's immune response, genetic factors, and predisposing health conditions. Studies conducted in Malaysia, India, and Brazil have recorded a significantly higher intensity of warning signs (90%) and other severe disease manifestations (15%) among patients with concurrent DENV infections [54; 55]. A major fraction of patients exhibited elevated creatinine levels, indicating potential kidney involvement, along with pleural effusion. Furthermore, the frequency of patients with severe thrombocytopenia was greater, highlighting the increased risk of haemorrhage and other blood complications [54; 55]. Given the multifactorial drivers, it is critical to include DENV co-infections as part of the routine dengue diagnosis to prevent the occurrence of severe dengue, characterized by severe plasma leakage, haemorrhagic manifestations, and organ impairment at the early stage [3]. Although atypical manifestations of dengue are uncommon, patients with concurrent DENV infections did exhibit hepatic, pulmonary, and renal complications [56].