Impact of Pre-existing Cross-Reactive Antibodies on Cyclic Dengue Outbreaks in the Hyperendemic Region of Bali, Indonesia.

The four serotypes of the dengue virus (DENV) cause a range of diseases ranging from mild fever to severe conditions. Understanding the immunological interactions among the four serotypes is crucial in comprehending the dynamics of serotype shifting during outbreaks in areas where all four serotypes co-circulate. Hence, we evaluated the neutralizing antibody and antibody-dependent enhancement responses against the four DENV serotypes using acute-phase plasma samples collected from 48 laboratory-confirmed dengue patients during a dengue outbreak in Bali, Indonesia in 2022. Employing single-round infectious particles to exclusively investigate immunogenicity to the structural surface proteins of DENV, which are the targets of antibodies, we found that individuals with a probable prior history of DENV-1 infection exhibited increased susceptibility to secondary DENV-3 infection, attributed to cross-reactive antibodies with limited neutralizing activity against DENV-3 (geometric mean 50% neutralization titer (GMNT50) = 47.6 ± 11.5). This susceptibility was evident in vitro, with a mean fold enhancement of 28.4 ± 33.9. Neutralization titers against DENV-3 were significantly lower compared to other serotypes (DENV-1 GMNT50 = 678.1 ± 9.0; DENV-2 GMNT50 = 210.5 ± 8.7; DENV-4 GMNT50 = 95.14 ± 7.0). We demonstrate that prior immunity to one serotype provides limited cross-protection against the other serotypes, influencing the dominant serotype in subsequent outbreaks. These findings underscore the complexity of dengue immunity and its implications for vaccine design and transmission dynamics in hyperendemic regions.

Evolution and immunopathology of chikungunya virus informs therapeutic development.

Chikungunya virus (CHIKV), a mosquito-borne alphavirus, is an emerging global threat identified in more than 60 countries across continents. The risk of CHIKV transmission is rising due to increased global interactions, year-round presence of mosquito vectors, and the ability of CHIKV to produce high host viral loads and undergo mutation. Although CHIKV disease is rarely fatal, it can progress to a chronic stage, during which patients experience severe debilitating arthritis that can last from several weeks to months or years. At present, there are no licensed vaccines or antiviral drugs for CHIKV disease, and treatment is primarily symptomatic. This Review provides an overview of CHIKV pathogenesis and explores the available therapeutic options and the most recent advances in novel therapeutic strategies against CHIKV infections.

Integrated systems immunology approach identifies impaired effector T cell memory responses as a feature of progression to severe dengue fever.

BACKGROUND: Typical symptoms of uncomplicated dengue fever (DF) include headache, muscle pains, rash, cough, and vomiting. A proportion of cases progress to severe dengue hemorrhagic fever (DHF), associated with increased vascular permeability, thrombocytopenia, and hemorrhages. Progression to severe dengue is difficult to diagnose at the onset of fever, which complicates patient triage, posing a socio-economic burden on health systems. METHODS: To identify parameters associated with protection and susceptibility to DHF, we pursued a systems immunology approach integrating plasma chemokine profiling, high-dimensional mass cytometry and peripheral blood mononuclear cell (PBMC) transcriptomic analysis at the onset of fever in a prospective study conducted in Indonesia. RESULTS: After a secondary infection, progression to uncomplicated dengue featured transcriptional profiles associated with increased cell proliferation and metabolism, and an expansion of ICOS+CD4+ and CD8+ effector memory T cells. These responses were virtually absent in cases progressing to severe DHF, that instead mounted an innate-like response, characterised by inflammatory transcriptional profiles, high circulating levels of inflammatory chemokines and with high frequencies of CD4low non-classical monocytes predicting increased odds of severe disease. CONCLUSIONS: Our results suggests that effector memory T cell activation might play an important role ameliorating severe disease symptoms during a secondary dengue infection, and in the absence of that response, a strong innate inflammatory response is required to control viral replication. Our research also identified discrete cell populations predicting increased odds of severe disease, with potential diagnostic value.

Genetic characterization of dengue virus 4 complete genomes from East Java, Indonesia.

Dengue is an endemic arboviral disease with continuous transmission in Indonesia for more than five decades. A recent outbreak in Jember, East Java province, demonstrated the predominance of DENV-4, a serotype known for its low global spread and limited transmission. While epidemiological factors such as new serotype introduction and lacking herd immunity may explain its predominance, viral factors may also contribute. Using next-generation sequencing, we generated 13 representative complete genomes of DENV-4 responsible for the outbreak. Phylogenetic and evolutionary analyses on complete genomes were performed to understand the spatial and temporal dynamics of the viruses. Further analyses were done to study amino acid variations in DENV genes, as well as the potential events of recombination and selection pressure within the genomes. We revealed the DENV-4 genetic factors that may lead to its predominance in the 2019 Jember dengue outbreak. A combination of selection pressure and mutational genetic changes may contribute to the DENV-4 predominance in East Java, Indonesia. The possible intra-serotype recombination events involving the non-structural protein 5 (NS5) gene were also observed. Altogether, these genetic factors may act as additional factors behind the complex dengue outbreak mechanism.

The role of mediator suppressor of cytokine signaling (SOCS), toll-like receptor 3 (TLR-3) and nuclear factor kappa B (NFκB) on cytokine production during dengue virus infection.

Inability to understand the pathogenesis of severe dengue, in particular the control mechanism of immune responses, has led to high mortality rate for patients with dengue shock syndrome (DSS). The aim of this study was to determine the control mechanism of cytokine production by mediator suppressor of cytokine signaling (SOCS), toll-like receptor 3 (TLR-3) and nuclear factor kappa B (NFκB) during DENV infection. Peripheral blood mononuclear blood cells (PBMC), isolated from healthy individuals, were infected with dengue virus (DENV)-2 strain SJN-006 Cosmopolitan genotype (isolated from Bali, Indonesia). The relative gene expression of SOCS-3, TLR-3, NFκB, and the cytokine genes (interleukin (IL)-6, IL-8, interferon inducible protein 10 (IP-10), and macrophage inflammatory protein-1 beta (MIP-1ß)) were measured using qRT-PCR at 6, 12 and 24 hours post infection (hpi). Student t-test and Mann-Whitney test were used to compare the gene expressions while causal correlations were analyzed using regression test and path analyses. DENV-2 infection increased the gene expression of SOCS-3, TLR-3, and NFκB after 12 and 24 hpi. The expression of IL-6, IL-8, IP-10, and MIP-1ß genes was increased and peaked at different times post-infection. NFκB and SOCS-3 genes likely have role in the upregulation of IL-8 and IL-6 gene expression, respectively. MIP-1ß gene expression was significantly induced by both NFκB and SOCS-3. In conclusion, our study suggested that SOCS-3, TLR-3, and NFκB are important in regulating the production of IL-6, IL-8, IP-10, MIP-1ß during early phase of DENV-2 infection. This enriches our understanding on pathogenesis pathway of DENV-associated cytokine storm.

Dengue virus population genetics in Yogyakarta, Indonesia prior to city-wide Wolbachia deployment.

Dengue has been endemic in Yogyakarta, Indonesia for decades. Here, we report the dengue epidemiology, entomology, and virology in Yogyakarta in 2016-2017, prior to the commencement of the Applying Wolbachia to Eliminate Dengue (AWED) randomized trial. Dengue epidemiological data were compiled and blood samples from dengue-suspected patients were tested for dengue virus (DENV). Ae. aegypti mosquito samples were caught from the field using BG-Sentinel traps and tested for the presence of DENV infection. Sequencing of the DENV E gene was used to determine the phylogeny and genotypes of circulating DENV. Within the last decade, the 2016-2017 dengue incidence was considered very high. Among the 649 plasma samples collected between March 2016-February 2017; and 36,910 mosquito samples collected between December 2016-May 2017, a total of 197 and 38 samples were DENV-positive by qRT-PCR, respectively. All four DENV serotypes were detected, with DENV-3 (n = 88; 44.67%) and DENV-1 (n = 87; 44.16%) as the predominant serotype, followed by DENV-4 (n = 12; 6.09%) and DENV-2 (n = 10; 5.08%). The Yogyakarta DENV-1 isolates were classified into Genotype I and IV, while DENV-2, DENV-3, and DENV-4 isolates were classified into the Cosmopolitan genotype, Genotype I, and Genotype II, respectively. Yogyakarta DENV isolates were closely related to Indonesian strains from neighboring Javanese cities, consistent with the endemic circulation of DENV on this highly populous island. Our study provides comprehensive baseline information on the DENV population genetic characteristics in Yogyakarta, which are useful as baseline data for the AWED trial and the future DENV surveillance in the city in the presence of a Wolbachia-infected Ae. aegypti population.

Continuous Circulation of Chikungunya Virus during COVID-19 Pandemic in Jambi, Sumatra, Indonesia.

Chikungunya fever is a self-limiting viral illness that is caused by the chikungunya virus (CHIKV). CHIKV is found in multiple provinces of Indonesia, with clustered local outbreaks. This case series investigates a local chikungunya outbreak during the COVID-19 pandemic, involving two virologically confirmed chikungunya cases found in Jambi, Sumatra, Indonesia in 2021 and the contact tracing of 65 people from the same neighborhood (one of which was also virologically confirmed with CHIKV). The two original cases were symptomatic with classic signs of chikungunya fever, while the CHIKV-positive neighbor was asymptomatic. Out of the 65 participants, chikungunya IgM was detected in seven (10.8%) people while chikungunya IgG was detected in six (9.2%) using capture ELISA. Dengue IgG was detected by rapid test in three (4.6%) of the participants, showcasing a history of dengue virus (DENV) infection along with the circulation of CHIKV in the area. A phylogenetic analysis demonstrates a close evolutionary relationship between all three 2021 Jambi CHIKV isolates and the 2015-2016 isolates from Jambi. This case series showcases the endemicity and persistent circulation of CHIKV in Jambi, leaving the area vulnerable to eminent outbreaks of chikungunya fever and doubling the burden of disease during the COVID-19 pandemic. Health staff training for case detection and notification, as well as an integrated vector surveillance should continue to be implemented to provide an early warning indicator of possible chikungunya outbreaks.

Combining rapid diagnostic tests to estimate primary and post-primary dengue immune status at the point of care.

BACKGROUND: Characterising dengue virus (DENV) infection history at the point of care is challenging as it relies on intensive laboratory techniques. We investigated how combining different rapid diagnostic tests (RDTs) can be used to accurately determine the primary and post-primary DENV immune status of reporting patients during diagnosis. METHODS AND FINDINGS: Serum from cross-sectional surveys of acute suspected dengue patients in Indonesia (N:200) and Vietnam (N: 1,217) were assayed using dengue laboratory assays and RDTs. Using logistic regression modelling, we determined the probability of being DENV NS1, IgM and IgG RDT positive according to corresponding laboratory viremia, IgM and IgG ELISA metrics. Laboratory test thresholds for RDT positivity/negativity were calculated using Youden's J index and were utilized to estimate the RDT outcomes in patients from the Philippines, where only data for viremia, IgM and IgG were available (N:28,326). Lastly, the probabilities of being primary or post-primary according to every outcome using all RDTs, by day of fever, were calculated. Combining NS1, IgM and IgG RDTs captured 94.6% (52/55) and 95.4% (104/109) of laboratory-confirmed primary and post-primary DENV cases, respectively, during the first 5 days of fever. Laboratory test predicted, and actual, RDT outcomes had high agreement (79.5% (159/200)). Among patients from the Philippines, different combinations of estimated RDT outcomes were indicative of post-primary and primary immune status. Overall, IgG RDT positive results were confirmatory of post-primary infections. In contrast, IgG RDT negative results were suggestive of both primary and post-primary infections on days 1-2 of fever, yet were confirmatory of primary infections on days 3-5 of fever. CONCLUSION: We demonstrate how the primary and post-primary DENV immune status of reporting patients can be estimated at the point of care by combining NS1, IgM and IgG RDTs and considering the days since symptoms onset. This framework has the potential to strengthen surveillance operations and dengue prognosis, particularly in low resource settings.

Hyperendemic Dengue and Possible Zika Circulation in the Westernmost Region of the Indonesian Archipelago.

The transmission of dengue and other medically important mosquito-borne viruses in the westernmost region of Indonesia is not well described. We assessed dengue and Zika virus seroprevalence in Aceh province, the westernmost area of the Indonesian archipelago. Serum samples collected from 199 randomly sampled healthy residents of Aceh Jaya in 2017 were analyzed for neutralizing antibodies by plaque reduction neutralization test (PRNT). Almost all study participants (198/199; 99.5%) presented with multitypic profiles of neutralizing antibodies to two or more DENV serotypes, indicating transmission of multiple DENV in the region prior to 2017. All residents were exposed to one or more DENV serotypes by the age of 30 years. The highest geometric mean titers were measured for DENV-4, followed by DENV-1, DENV-2 and DENV-3. Among a subset of 116 sera, 27 neutralized ZIKV with a high stringency (20 with PRNT90 > 10 and 7 with PRNT90 > 40). This study showed that DENV is hyperendemic in the westernmost region of the Indonesian archipelago and suggested that ZIKV may have circulated prior to 2017.

Co-Circulation of Chikungunya and Multiple DENV Serotypes and Genotypes, Western Indonesia 2015-2016.

Dengue is a mosquito-borne disease of public health concern affecting tropical and subtropical countries, including Indonesia. Although studies on dengue epidemiology have been undertaken in Indonesia, data are lacking in many areas of the country. The aim of this study was to determine dengue virus (DENV) and chikungunya virus (CHIKV) molecular epidemiology in western regions of the Indonesian archipelago. A one-year prospective study was conducted in Aceh and Jambi in 2015 and 2016, respectively, where patients with dengue-like illness were enrolled. Of 205 patients recruited, 29 and 27 were confirmed with dengue in Aceh and Jambi, respectively, and three from Jambi were confirmed with chikungunya. DENV-1 was the predominant serotype identified in Aceh while DENV-2 was predominant in Jambi. All DENV-1 and DENV-2 from both regions were classified as Genotype I and Cosmopolitan genotype, respectively, and all DENV-3 viruses from Jambi were Genotype I. Some viruses, in particular DENV-1, displayed a distinct lineage distribution, where two DENV-1 lineages from Aceh were more closely related to viruses from China instead of Jambi highlighting the role of travel and flight patterns on DENV transmission in the region. DENV-2 from both Aceh and Jambi and DENV-3 from Jambi were all closely related to Indonesian local strains. All three CHIKV belonged to Asian genotype and clustered closely with Indonesian CHIKV strains including those previously circulating in Jambi in 2015, confirming continuous and sustainable transmission of CHIKV in the region. The study results emphasize the importance of continuous epidemiological surveillance of arboviruses in Indonesia and simultaneous testing for CHIKV among dengue-suspected patients.

Molecular epidemiology of dengue in a setting of low reported endemicity: Kupang, East Nusa Tenggara province, Indonesia.

BACKGROUND: Most regions in Indonesia experience annual dengue epidemics. However, the province of East Nusa Tenggara has consistently reported low incidence. We conducted a dengue molecular epidemiology study in Kupang, the capital of the province. METHODS: Dengue patients were recruited from May 2016 to September 2017. Dengue virus (DENV) screening was performed using NS1 and immunoglobulin G (IgG)/IgM detection. Serotype was determined using reverse transcription polymerase chain reaction and the envelope genes were sequenced to infer the genetic identity and phylogeny. RESULTS: From 119 patients, dengue was confirmed in 62 (52%). Compared with official data, underreporting of dengue incidence was observed. The majority (36%) of patients were children <10 y of age. Most patients (80%) experienced mild fever. All serotypes were detected, with DENV-3 as the predominant (57%). Kupang DENV-1 isolate was classified as genotype IV, an old and endemic strain, DENV-2 as cosmopolitan, DENV-3 as genotype I and DENV-4 as genotype II. Most isolates showed relatively low evolutionary rates and are closely related with strains from Bali and Timor Leste. CONCLUSIONS: The low dengue incidence was most likely caused by sustained local circulation of endemic viruses. This study provides information on the epidemiology of dengue in a low-endemicity setting that should help future mitigation and disease management.

Molecular epidemiology of dengue in North Kalimantan, a province with the highest incidence rates in Indonesia in 2019.

OBJECTIVES: Dengue is endemic to Indonesia, a country that has largely varied geographical and demographic conditions across different regions. In 2019, dengue epidemic occurred in North Kalimantan province and recorded as the highest incidence rate in Indonesia. This study aims to investigate the molecular epidemiology of dengue during outbreak in the province and compare the epidemiological characteristics between two cities/towns in North Kalimantan, namely Malinau, an inland town surrounded by a dense rainforest, and Tarakan, an island city. METHODS: A cross sectional study was conducted between September 2018 and July 2019. Dengue-like illness patients were recruited in hospitals and tested for dengue NS1 and IgG/IgM. Serological prevalence was measured using IgG ELISA, dengue virus (DENV) serotyping was conducted using RT-PCR and Envelope gene sequencing was performed to infer the virus origins and phylogeny. Clinical, demographical, and diagnostics data were also recorded and analyzed. RESULTS: We recruited 523 patients, 261 from Malinau and 262 from Tarakan. Among them, 349 patients were confirmed dengue. Cases in Malinau had a higher proportion of confirmed dengue (82.0%) compared to those in Tarakan (51.5%). Cases in Malinau were more likely to be dengue hemorrhagic fever with more severe hematological features compared to those in Tarakan. All four DENV serotypes were detected in both cities, the most prevalent serotype being DENV-2. The genetic characteristics of the viruses in the two towns was similar except for DENV-3. No sylvatic DENV was detected as well as alphaviruses and non-dengue flaviviruses during the outbreak. CONCLUSIONS: The molecular epidemiology of dengue in North Kalimantan revealed the similar virological characteristics but different clinical and demographic aspects in Malinau and Tarakan. The distinct dengue dynamics between different regions of Indonesia is prominent and this knowledge will be important for understanding future patterns of DENV transmission in the region.

Comparative cytokine profiling identifies common and unique serum cytokine responses in acute chikungunya and dengue virus infection.

BACKGROUND: Infection by chikungunya (CHIKV) and dengue virus (DENV) can cause a wide spectrum of clinical features, many of which are undifferentiated. Cytokines, which broadly also include chemokines and growth factors, have been shown to play a role in protective immunity as well as DENV and CHIKV pathogenesis. However, differences in cytokine response to both viruses remain poorly understood, especially in patients from countries where both viruses are endemic. Our study is therefore aimed to provide a comparative profiling of cytokine response induced by acute DENV and CHIKV infections in patients with similar disease stages and in experimental in vitro infections. METHODS: By using multiplex immunoassay, we compared host cytokine profiles between acute CHIKV and DENV infections by analysing serum cytokine levels of IL-1α, IL-4, IL-5, IL-8, IL-13, RANTES, MCP-3, eotaxin, PDGF-AB/BB, and FGF-2 from the sera of acute chikungunya and dengue fever patients. We further investigated the cytokine profile responses using experimental in vitro CHIKV and DENV infections of peripheral blood mononuclear cells (PBMCs). RESULTS: We found that both CHIKV and DENV-infected patients had an upregulated level of IL-8 and IL-4, with the highest IL-4 level observed in DENV-2 infected patients. Higher IL-8 level was also correlated with lower platelet count in dengue patients. IL-13 and MCP-3 downregulation was observed only in chikungunya patients, while conversely PDGF-AB/BB and FGF-2 downregulation was unique in dengue patients. Age-associated differential expression of IL-13, MCP-3, and IL-5 was also observed, while distinct kinetics of IL-4, IL-8, and FGF-2 expression between CHIKV and DENV-infected patients were identified. Furthermore, the unique pattern of IL-8, IL-13 and MCP-3, but not IL-4 expression was also recapitulated using experimental in vitro infection in PBMCs. CONCLUSIONS: Taken together, our study identified common cytokine response profile characterized by upregulation of IL-8 and IL-4 between CHIKV and DENV infection. Downregulation of IL-13 and MCP-3 was identified as a unique cytokine response profile of acute CHIKV infection, while distinct downregulation of PDGF-AB/BB and FGF-2 characterized the response from acute DENV infection. Our study provides an important overview of the host cytokine responses between CHIKV and DENV infection, which is important to further understand the mechanism and pathology of these diseases.

Spatiotemporal Heterogeneity of Zika Virus Transmission in Indonesia: Serosurveillance Data from a Pediatric Population.

The presence of Zika virus (ZIKV) in Indonesia has been recognized since the 1970s, but its transmission dynamics there have been poorly understood. To understand more fully the geographic distribution and burden of ZIKV infection, we performed retrospective serological tests on specimens collected from asymptomatic children age 5 to 9 years old living at 30 sites in 14 provinces. Of 870 serum samples tested, 9.2% were found to be positive for anti-ZIKV antibodies, as confirmed by plaque reduction neutralization assays. This was the same overall prevalence reported previously for 1- to 4-year-old children collected at the same sites at the same time. Together with geographic differences in seroprevalence between the age groups, these data suggest that, although ZIKV might be endemic in Indonesia, its occurrence has been focal and episodic.

[6]-Gingerol Inhibits Chikungunya Virus Infection by Suppressing Viral Replication.

Chikungunya (CHIK) is a reemerging arboviral disease caused by chikungunya virus (CHIKV) infection. The disease is clinically hallmarked by prolonged debilitating joint pain. Currently, there is no specific antiviral medication nor commercial vaccine available for treatment of the disease, which makes the discovery or development of specific anti-CHIKV compounds a priority. Ginger (Zingiber officinale Roscoe) is widely known for its various health benefits. The compound [6]-gingerol is the main active ingredient found in ginger. This study sought to determine the potential of [6]-gingerol antiviral activity against CHIKV infection using in vitro human hepatocyte HepG2 cells. The antiviral activity mechanism was investigated using direct virucidal and four indirect (pre-, post-, full-, and prevention) treatment assays. [6]-Gingerol showed weak virucidal activity but significant indirect antiviral activity against CHIKV through post- and full treatment with IC50 of 0.038 mM and 0.031 mM, respectively, without showing cell cytotoxicity. The results indicated that [6]-gingerol inhibits CHIKV infection through suppression of viral replication. Together, this study confirms the potential use of [6]-gingerol for CHIK antiviral compound.

Outbreak of severe dengue associated with DENV-3 in the city of Manado, North Sulawesi, Indonesia.

BACKGROUND: In early 2019, an outbreak of severe dengue was reported in Manado, North Sulawesi Province, Indonesia. This epidemic raised public concern and recorded the highest number of cases in the last 10 years. This study aimed to determine the clinical spectrum, disease aetiology and virological characteristics associated with this outbreak of severe dengue. METHODS: Dengue was diagnosed using non-structural protein 1 detection, reverse transcription polymerase chain reaction and immunoglobulin (Ig)G/IgM serology. Envelope gene sequencing was conducted to determine the phylogeny of the dengue virus (DENV). RESULTS: In total, 146 patients with a median age of 8 years (interquartile range IQR 5-11 years) were recruited. Most patients experienced expanded dengue syndrome, characterized by severe organ involvement including liver enlargement, stomach ache and coagulation problems. During the outbreak, DENV-3 was the dominant serotype (75.9%). Smaller numbers of DENV-1, -2 and -4 were also detected. Phylogenetically, the dominant DENV-3 strains were grouped in multiple clusters and were related to other Indonesian strains, suggesting the emergence of heterogenous local viruses. CONCLUSION: The occurrence of an outbreak of severe dengue in Manado was confirmed, and DENV-3 was found to be the dominant serotype during the outbreak. This study shows the benefits of virological surveillance in understanding the aetiological agents responsible for outbreaks of severe dengue.

Assessment of dengue and COVID-19 antibody rapid diagnostic tests cross-reactivity in Indonesia.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic remains ongoing around the world, including in areas where dengue is endemic. Dengue and COVID-19, to some extent, have similar clinical and laboratory features, which can lead to misdiagnosis, delayed treatment and patient's isolation. The use of rapid diagnostic tests (RDT) is easy and convenient for fast diagnosis, however there may be issues with cross-reactivity with antibodies for other pathogens. METHODS: We assessed the possibility of cross-reactivity between SARS-CoV-2 and dengue antibodies by: (1) testing five brands of COVID-19 IgG / IgM RDTs on 60 RT-PCR-confirmed dengue samples; (2) testing 95 RT-PCR-confirmed COVID-19 samples on dengue RDT; and (3) testing samples positive for COVID-19 IgG and/or IgM on dengue RDT. RESULTS: We observed a high specificity across all five brands of COVID-19 RDTs, ranging from 98.3 to 100%. Out of the confirmed COVID-19 samples, one patient tested positive for dengue IgM only, another tested positive for dengue IgG only. One patient tested positive for dengue IgG, IgM, and NS1, suggesting a co-infection. In COVID-19 IgG and/or IgM samples, 6.3% of COVID-19 IgG-positive samples also tested positive for dengue IgG, while 21.1% of COVID-19 IgM-positive samples also tested positive for dengue IgG. CONCLUSION: Despite the high specificity of the COVID-19 RDT, we observed cross-reactions and false-positive results between dengue and COVID-19. Dengue and COVID-19 co-infection was also found. Health practitioners in dengue endemic areas should be careful when using antibody RDT for the diagnosis of dengue during the COVID-19 pandemic to avoid misdiagnosis.

Covid-19 and dengue: Double punches for dengue-endemic countries in Asia.

The coronavirus disease 2019 (Covid-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an international public health crisis with devastating effects. In particular, this pandemic has further exacerbated the burden in tropical and subtropical regions of the world, where dengue fever, caused by dengue virus (DENV), is already endemic to the population. The similar clinical manifestations shared by Covid-19 and dengue fever have raised concerns, especially in dengue-endemic countries with limited resources, leading to diagnostic challenges. In addition, cross-reactivity of the immune responses in these infections is an emerging concern, as pre-existing DENV-antibodies might potentially affect Covid-19 through antibody-dependent enhancement. In this review article, we aimed to raise the issue of Covid-19 and dengue fever misdiagnosis, not only in a clinical setting but also with regards to cross-reactivity between SARS-CoV-2 and DENV antibodies. We also have discussed the potential consequences of overlapping immunological cascades between dengue and Covid-19 on disease severity and vaccine development.