When both DENV and SARS-CoV-2 infect the same host, their respective immune responses can intersect, potentially amplifying pathological outcomes. In a recent Brazilian cohort, patients co-infected with dengue and COVID-19 exhibited significantly elevated circulating levels of IL-1β, TNF-α, and IL-10 compared to those infected solely with SARS-CoV-2 (3). These findings indicate the concurrent activation of pro-inflammatory and anti-inflammatory pathways, which could exacerbate vascular injury and increase the risk of multi-organ dysfunction.

Immune crosstalk occurs bidirectionally. In vitro and murine studies show antibodies to the SARS-CoV-2 spike receptor-binding domain cross-react with DENV E and NS1 proteins, suppressing dengue replication and reducing hemorrhage and vascular permeability (32). Human COVID-19 convalescent sera also neutralize DENV in cell culture, suggesting prior SARS-CoV-2 infection or vaccination may confer partial dengue immunity. Conversely, DENV-induced antibodies cross-react with SARS-CoV-2 antigens, complicating diagnostics and raising theoretical ADE concerns. While no clinical evidence links pre-existing dengue immunity to worse COVID-19 outcomes (13), the risk remains unresolved. This interplay of cross-neutralization, possible ADE, and convergent inflammatory signaling requires further study across diverse epidemiological and genetic contexts.

From a public health perspective, dengue–COVID-19 co-infection burdens both diagnosis and control efforts. In endemic areas with active SARS-CoV-2 transmission, clinicians should suspect co-infection in febrile patients due to overlapping symptoms (fever, myalgia, headache, rash) (13) and shared lab findings (leukopenia, thrombocytopenia, elevated transaminases). Accurate diagnosis demands simultaneous molecular or antigen-based testing (RT-qPCR or rapid antigen for SARS-CoV-2; NS1 antigen or RT-qPCR for dengue within five days), followed by IgM/IgG serology. Modeling and empirical analyses suggest that diagnostic strategies focused on a single pathogen can miss a substantial fraction of co-infections (43–45).

The COVID-19 pandemic severely disrupted global efforts to control vector-borne diseases. Border closures, lockdowns, and movement restrictions halted entomological surveillance and community vector control, while prolonged household water storage during stay-at-home orders created ideal breeding sites for Aedes. Although many countries reported >40% declines in dengue notifications in 2020, sharp increases occurred in Peru, Singapore, and parts of India (33). Machine-learning and statistical analyses of dengue notifications, human mobility data and COVID-19 non-pharmaceutical interventions from multiple endemic countries suggest that dengue resurgence often follows rebounds in human mobility during warm, humid periods (33, 46–48).

Given that dengue and COVID-19 disproportionately affect low-resource settings, simultaneous outbreaks place severe strain on healthcare infrastructure, including hospital beds, intensive care units, and laboratory testing capacity. Immediate public health priorities should therefore include reinstating comprehensive vector control programs, integrating arbovirus and respiratory disease surveillance systems, and deploying cost-effective multiplex rapid diagnostic tests. Such integrated measures are essential to mitigate the combined clinical and epidemiological impacts of dengue–COVID–19 co-infection (6, 49, 50).

Current evidence unequivocally demonstrates that dengue–COVID–19 co-infection occurs and can significantly exacerbate disease outcomes; however, the clinical impact varies widely depending on local contexts. Some cohorts report notably high mortality rates approaching 50% (3), while others document mild or uncomplicated recoveries (14). Cross-reactive antibodies further complicate the diagnostic landscape but may also confer partial immune protection against subsequent infections (51). These divergent findings underscore critical knowledge gaps in pathogenesis, host immune response variability, and healthcare system resilience. Additionally, emerging epidemiological models highlight population-level factors, including holiday travel patterns, climatic anomalies, and rebounds in human mobility, synchronizing dengue and SARS-CoV-2 transmission cycles. Thus, future preventive strategies should integrate robust vector control measures, comprehensive surveillance of respiratory viruses, and targeted behavioral interventions (5).

As dengue continues its geographic expansion and SARS-CoV-2 transitions to endemicity, instances of dual infections are likely to increase. Therefore, elucidating the clinical trajectories, immunological interactions, and optimal management strategies for dengue–COVID–19 co-infection is an urgent priority (52). This is essential not only for effective clinical triage but also for informing policy decisions in resource-limited regions disproportionately affected by these overlapping health crises. The review presented here synthesizes current insights on the epidemiology, clinical severity, immunopathogenesis, and diagnostic challenges associated with co-infection. It outlines critical research directions to address this emerging global health challenge.

Co-infection and pre-existing immunity exert intense selective pressures, driving pathogens to adapt to their host’s immune landscape. When two viruses circulate simultaneously, each can evolve in response to immune pressures shaped by the other. Dengue virus (DENV), with four antigenically distinct serotypes, illustrates this dynamic: infection by one serotype induces durable homotypic immunity via serotype-specific neutralizing antibodies, forcing each serotype to evade these antibodies or risk displacement. A 20-year analysis of 1,944 DENV isolates from Thailand (1994–2014) revealed consistent antigenic drift across all serotypes, reflecting adaptation to herd immunity, and transient antigenic convergence coinciding with epidemic peaks (53). Such convergence may enable viral lineages to exploit partial cross-immunity, boosting their competitiveness and driving larger outbreaks.

Notably, Thailand’s largest dengue epidemics were characterized by low antigenic diversity, with a single lineage that was adept at evading prevailing population immunity. Conversely, periods of lower transmission intensity exhibited greater antigenic diversity, indicating that no single variant possessed a significant immunological advantage. This cyclical pattern highlights the intricate interplay between viral evolution and host immune pressure: DENV serotypes regularly diversify antigenically to circumvent sterilizing immunity yet intermittently converge to exploit the residual cross-reactivity generated by preceding serotypes. This ongoing dynamic can be viewed as an immunological “arms race,” wherein viral adaptation and host immune responses continually influence each other’s evolution (53).

The phenomenon of antibody-dependent enhancement (ADE) in dengue further imposes distinct selective pressures on viral evolution. During secondary dengue infections, pre-existing heterotypic antibodies bind to a different DENV serotype without fully neutralizing it, facilitating enhanced viral entry into Fcγ-receptor-bearing cells. This process results in increased viral replication, elevated viral loads, and heightened immunopathology (53). In regions such as Bangkok, approximately 90–95% of hospitalized dengue patients experience secondary or subsequent dengue virus (DENV) infections, highlighting the prevalence of immune-primed populations that frequently encounter the virus. Consequently, DENV has evolved not only to evade existing immune responses but also to exploit partial cross-reactivity, thereby enhancing replication and transmission (54, 55).

During high dengue transmission, variants with optimal antigenic divergence (distinct enough to evade neutralizing antibodies yet similar enough to exploit ADE) gain a selective advantage and may quickly dominate. This balance reflects a trade-off between immune evasion and use of cross-reactive antibodies, creating a genetic and antigenic “arms race.” Over time, DENV serotypes accumulate antigenic changes to escape homotypic immunity, but antigenic mapping shows transient convergence, where lineages regain partial similarity to exploit cross-reactive antibodies and boost transmission (53). These quantitative findings illustrate clearly how host immune pressures drive the continual evolutionary turnover and antigenic modulation observed in dengue virus populations.

SARS-CoV-2 has likewise evolved under strong host immune pressures, with variants of concern (Alpha, Beta, Delta, Omicron, and sublineages) adapting mainly to evade neutralizing antibodies, and to a lesser extent, T-cell responses from prior infection or vaccination (56, 57). In immune populations, antibody escape is a key driver of variant success. In dengue-endemic regions, SARS-CoV-2 co-circulation with DENV may introduce additional selective pressures through cross-reactive immunity.

Mallick and Biswas (10) report that successive SARS-CoV-2 variants have acquired spike protein mutations within regions targeted by dengue-induced cross-reactive antibodies, reducing binding affinity. From Alpha (B.1.1.7) and Delta (B.1.617.2) to Omicron sublineages (BA.1, BA.2), amino acid substitutions consistently overlapped with dengue antibody epitopes. Omicron variants (2022–2023) showed ≥50% lower cross-reactivity to dengue-positive sera than earlier variants, confirmed by in vitro assays demonstrating reduced binding of dengue-immune human sera to mutated spike epitopes. These data suggest SARS-CoV-2 has accumulated antigenic changes to evade dengue-elicited antibodies, reflecting evolutionary pressure in dengue-experienced populations (10). Reciprocal selective pressures may allow dengue and SARS-CoV-2 to influence each other’s antigenic evolution, potentially producing variants with greater immune escape, transmissibility, or altered virulence. This underscores the need for integrated surveillance addressing the interactive evolutionary dynamics of co-circulating viruses (10, 56).

In overlapping dengue and COVID-19 epidemics, selective pressures may act on both viruses at the population and within-host levels. The immune environment shaped by one pathogen can influence the other’s evolution. In hosts with dengue immunity, SARS-CoV-2 may encounter cross-reactive antibodies or memory T cells that favor variants able to evade them; similarly, DENV infecting COVID-convalescent hosts may face coronavirus-induced immunity. While direct evidence of mutations from dengue–COVID interactions is lacking, analogous co-infections suggest plausibility. Immune cross-reactivity could drive “escape” from shared epitopes. SARS-CoV-2 variants with mutations in DENV-like regions, or DENV variants evading anti-Spike antibodies, may gain a fitness advantage. This remains speculative but is a key evolutionary question.

Multiple studies have explored how different SARS-CoV-2 variants cross-react with the four dengue virus serotypes. For example, Nath et al. (42) found that COVID-19 convalescent sera from early in the pandemic (Wuhan strain period) frequently showed dengue cross-reactivity: 93% of SARS-CoV-2 antibody–positive samples gave positive results in dengue serology, and these sera could neutralize DENV-1 in vitro (42). Recent investigations by Mallick & Biswas (10) compared antibodies from patients infected by various SARS-CoV-2 variants against all four DENV serotypes. Notably, they report that antibodies generated during earlier waves (e.g. the original Wuhan strain and Delta variant) were broadly cross-reactive and could neutralize all four DENV serotypes (58, 59). By contrast, antibodies from Omicron-wave infections showed much narrower dengue cross-reactivity (58, 59). For instance, Omicron-era COVID-19 sera in one study retained some cross-neutralizing activity against DENV-1, DENV-2, and DENV-4, but failed to neutralize DENV-3 effectively. This aligns with the observation that post-Omicron COVID-19 antibodies are less cross-reactive with dengue compared to those from earlier variants (58, 59).

Quantitative differences in binding/neutralization have been documented. In a 2022 cohort, virtually all COVID-19 convalescents had dengue-cross-reactive antibodies (often without prior DENV exposure) (42). However, by 2022–2023 (Omicron era), only ~41.5% of COVID-19 sera showed dengue cross-reactivity, while the remaining ~58.5% were “DENV-non-cross-reactive” (60). Crucially, Omicron-era cross-reactive sera (the 41.5% subset) neutralized all DENV serotypes (1–4), mirroring the broad cross-neutralization seen with earlier variants (60). In contrast, the Omicron-era non-cross-reactive sera still cross-neutralized DENV-1, -2, and -4 to some extent but failed to neutralize DENV-3, instead enhancing DENV-3 infection via ADE (evidenced by significantly higher DENV-3 viral titers in cell culture) (60). This serotype-specific loss of neutralization (predominantly affecting DENV-3) is a consistent pattern: Mallick and colleagues observed that earlier variant antibodies (Alpha/Delta) were cross-reactive enough to neutralize even DENV-3, whereas Omicron variant antibodies lacked this capacity, correlating with a global surge in DENV-3 cases during the Omicron wave (58, 59). Emerging data from other groups (including preprints) further support these trends. For example, there are indications that the Omicron variant (or Omicron-specific boosters) elicit lower titers of dengue-cross-reactive antibodies than prior variants or vaccines targeting earlier strains (61). Overall, the pattern that arises is that successive SARS-CoV-2 variants, especially Omicron, have progressively reduced serological cross-reactivity to DENV, with specific gaps such as markedly diminished cross-neutralization of DENV-3 by Omicron-era antibodies (58, 59). Such findings underscore how viral evolution under selective pressure may alter immunological crosstalk between COVID-19 and dengue.

The pandemic reshaped the ecological and epidemiological context for both viruses. COVID-19 interventions (lockdowns, travel restrictions, masking) sharply reduced dengue transmission, acting as a bottleneck or selective sweep. An estimated 0.72 million fewer dengue cases occurred globally in 2020, with many countries seeing 40–60% lower incidence and some experiencing complete seasonal suppression (33, 46). This likely reduced viral genetic diversity and relaxed selection, while creating an “immunity gap” as fewer people acquired dengue immunity, potentially fueling larger outbreaks when transmission resumed. As mobility returned, rare or newly introduced strains could spread rapidly in naive populations, as seen with post-2021 resurgences of specific DENV serotypes. Prolonged lapses in mosquito control may also have favored vector–virus pairs adapted to peri-domestic settings.

For SARS-CoV-2, variant emergence (Alpha, Delta, Omicron, etc.) has been driven mainly by immune pressure from infections and vaccination. Whether dengue-specific factors influenced its evolution is unclear, though in dengue-endemic regions, baseline immune status from tropical infections could affect which variants spread. No evidence indicates that SARS-CoV-2 evolved differently in areas with high dengue incidence, but the question remains open. Epidemiologically, some studies report increased severe dengue after COVID-19 waves (62), suggesting possible effects via immune suppression or healthcare strain. Early speculation that dengue exposure might protect against COVID-19 has been refuted by cohort data showing the opposite: that prior dengue increases COVID-19 risk (50, 57). Unresolved questions include whether co-infection drives viral mutation within hosts (e.g., higher SARS-CoV-2 load or diversity) and whether flavivirus-immune populations shape SARS-CoV-2 antigenic sites over time. The evolutionary and genetic consequences of dengue–COVID-19 co-infection remain poorly defined and require targeted study.

Co-infection is linked to more severe outcomes than single infections (16, 50). Systematic analyses report frequent complications, including shock, ARDS, severe organ involvement, and death. A systematic review found high rates of thrombocytopenia and dyspnea, with some cases progressing to septic shock and multi-organ failure (16). In Colombia, concurrent DENV–SARS-CoV-2 infection significantly increased severe dengue manifestations (hemoconcentration, hypotension, mucosal bleeding, persistent vomiting) meeting hemorrhagic fever or “severe dengue” criteria more often than in typical dengue. These patients were also more likely to develop dengue shock syndrome and other warning signs, indicating COVID-19 can worsen dengue’s course (63). Conversely, in Singapore, adults with recent dengue had a 3.3-fold higher risk of severe COVID-19 outcomes when later infected with SARS-CoV-2 (64). This bidirectional aggravation likely reflects compounded inflammation and cumulative organ strain, underscoring the need for aggressive monitoring and supportive care in dengue–COVID co-morbidity.

The clinical severity of co-infection stems from complex immunological crosstalk. Both SARS-CoV-2 and DENV elicit strong innate and adaptive responses, dysregulate Type I interferon pathways, and can trigger cytokine storms and autoantibody production; combined, these effects may amplify hyperinflammation. A key concern is antibody-dependent enhancement (ADE) and cross-reactivity. In dengue, non-neutralizing antibodies from prior infection can facilitate viral entry into Fc-receptor–bearing cells, worsening the disease. This raises the question: could dengue antibodies enhance SARS-CoV-2 infection, or vice versa? Evidence is mixed. Pre-existing anti-DENV IgG has been hypothesized to bind SARS-CoV-2 and exacerbate COVID-19 via ADE (62), supported by epidemiological patterns and mechanistic parallels between flavivirus and coronavirus antibodies. Conversely, Cheng et al. found SARS-CoV-2–elicited antibodies (notably anti–Spike RBD) cross-react with DENV antigens, neutralize DENV in vitro, and reduce dengue-induced vascular leak in mice (39). Sera from COVID-19 patients also showed DENV-neutralizing activity. In contrast, a non-peer-reviewed report suggests SARS-CoV-2 antibodies could enhance DENV-2 infection via ADE. Whether dengue antibodies intensify COVID-19 remains under investigation; the Singapore cohort indicates worse COVID-19 outcomes in dengue-immune individuals (64), but direct immunological proof is lacking.

Overall, cross-reactive antibodies and T cells may confer partial cross-protection in some contexts yet worsen disease in others. This duality, alongside the potential for co-infection to trigger both dengue’s vascular leak and SARS-CoV-2’s hyperinflammatory lung injury, underscores the need to clarify how one virus modulates immune responses to the other.

The interplay between dengue and COVID-19 extends beyond biology to epidemiological and public health dynamics. Measures implemented to control COVID-19 have profoundly impacted dengue epidemics, illustrating the intertwined nature of these two diseases at the population level. Strict COVID-19 control policies, such as lockdowns, social distancing measures, school closures, and travel bans, led to marked declines in dengue cases in many regions during 2020. Reduced human movement led to fewer interactions between humans and mosquito vectors in workplaces, schools, and transit areas, thereby lowering dengue transmission. A statistical study in Latin America and Southeast Asia confirmed significantly fewer dengue cases in places with strong mobility restrictions, suggesting human mobility and congregation sites (e.g., schools, markets) are critical drivers of dengue spread, an insight gained incidentally through the COVID experience. These findings indicate that future vector-control approaches should target community gathering sites (47, 65).

COVID-19 measures had dual eco-epidemiological effects. Concurrent epidemics strained healthcare systems, particularly in resource-limited settings, diverting resources from dengue control. Many low- and middle-income countries reassigned staff, hospital beds, and labs to COVID-19, reducing dengue surveillance and vector control (breeding site removal, insecticide spraying, community education). Fear of COVID-19 led some febrile patients to avoid hospitals, delaying dengue diagnosis and treatment. Symptom overlap and lab overload raised concerns about misdiagnosis (66). Cross-reactivity in tests has been documented: SARS-CoV-2 can cause false-positive dengue serology, and dengue antibodies can cause false-positive COVID-19 antibody results (51). Such confusion risks inappropriate management, e.g., IV fluids for presumed dengue in COVID-19 pneumonia or steroids for presumed COVID-19 in dengue, both of which are potentially harmful.

These challenges highlight the need for integrated disease management during syndemics. Some regions acted proactively; in Sri Lanka, outreach campaigns urged febrile patients to seek dengue testing, and despite fewer cases, severe dengue and death rates did not rise in 2020, indicating reduced transmission rather than significant under-reporting (65). Concurrent dengue and COVID-19 outbreaks strained fragile healthcare systems (49), with resource-limited settings facing COVID-19 surges alongside seasonal dengue. Responses included establishing shared fever clinics and maintaining blood bank supplies for severe dengue, despite reduced donor numbers during lockdowns. Clinical care required balancing aggressive fluids for dengue shock with fluid restriction in severe COVID-19. Key lessons include sustaining vector control during respiratory pandemics and strengthening surveillance to detect spikes promptly.

The eco-epidemiological interaction also has socioeconomic dimensions: lockdowns reduced dengue transmission in many regions, yet as restrictions lifted, the potential for dengue resurgence increased. Since 2021, some countries have experienced dengue outbreaks, likely due to accumulated population susceptibility and the reintroduction of the virus through travel (67, 68). Thus, the dengue–COVID syndemic demonstrated that disease control strategies are interconnected; interventions targeting one disease can have both beneficial and adverse collateral effects on another, highlighting the necessity of holistic approaches that address both pathogens simultaneously, particularly in low-resource contexts.

As shown in Figure 1, the global distribution map illustrates how COVID-19 pandemic interventions influenced dengue transmission patterns worldwide. Countries marked green experienced significant reductions in dengue cases, attributed to stringent mobility restrictions and lockdown measures that indirectly reduced human-vector interactions. Conversely, nations highlighted in red reported increases, potentially due to disrupted vector control or altered human behaviors, such as increased household water storage during prolonged lockdowns. This visual evidence highlights the intricate interplay between COVID-19 public health interventions and dengue epidemiology, underscoring the importance of integrating epidemiological data and targeted vector-control strategies to address dual epidemics effectively (33, 65, 67, 69).

It is worth noting that Figure 1 presents aggregated national epidemiological data that illustrate broad trends in dengue incidence during the COVID-19 pandemic (2020–2021). In contrast, Table 1 summarizes individual clinical cases and smaller cohort studies of dengue–COVID–19 coinfection. These differences reflect distinct purposes and analytical scales rather than inconsistencies: Table 1 provides detailed clinical insights at the individual-case level, whereas Figure 1 emphasizes population-level epidemiological trends derived from national surveillance data (3, 13, 14, 16, 69).

Our critical appraisal of dengue–COVID–19 co-infection reveals numerous gaps in understanding, which we propose as priorities for future investigation: