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• Published: 28 June 2019

Cross-serotype interactions and disease outcome prediction of dengue infections in Vietnam

• R. Aguas 1 , 3 , 4 ,
• I. Dorigatti   ORCID: orcid.org/0000-0001-9959-0706 1 ,
• L. Coudeville 2 ,
• C. Luxemburger 2 &
• N. M. Ferguson   ORCID: orcid.org/0000-0002-1154-8093 1  

Scientific Reports volume  9 , Article number:  9395 ( 2019 ) Cite this article

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• Viral infection

Dengue pathogenesis is extremely complex. Dengue infections are thought to induce life-long immunity from homologous challenges as well as a multi-factorial heterologous risk enhancement. Here, we use the data collected from a prospective cohort study of dengue infections in schoolchildren in Vietnam to disentangle how serotype interactions modulate clinical disease risk in the year following serum collection. We use multinomial logistic regression to correlate the yearly neutralizing antibody measurements obtained with each infecting serotype in all dengue clinical cases collected over the course of 6 years (2004–2009). This allowed us to extrapolate a fully discretised matrix of serotype interactions, revealing clear signals of increased risk of clinical illness in individuals primed with a previous dengue infection. The sequences of infections which produced a higher risk of dengue fever upon secondary infection are: DEN1 followed by DEN2; DEN1 followed by DEN4; DEN2 followed by DEN3; and DEN4 followed by DEN3. We also used this longitudinal data to train a machine learning algorithm on antibody titre differences between consecutive years to unveil asymptomatic dengue infections and estimate asymptomatic infection to clinical case ratios over time, allowing for a better characterisation of the population’s past exposure to different serotypes.

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Introduction.

Dengue infections are the most common vector borne viral infections worldwide, with approximately one half of the world population at risk of acquiring a dengue infection 1 , with 390 million new infections estimated to occur in tropical and subtropical countries each year, of which one fourth to one third are clinical 2 , 3 . The dengue virus (DENV) is a single-stranded, positive-sense RNA virus of the Flavivirus genus that exists in the form of 4 distinct (but closely related) serotypes – DENV1 to DENV4. All serotypes co-circulate in hyperendemic areas causing periodic acute epidemics with significant occurrence of dengue fever and dengue haemorrhagic fever cases, with cyclical replacement of the dominant serotype over time 4 , 5 . These oscillatory dynamics have been postulated to be driven by cross-protection across serotypes and/or enhancement of infection by heterologous DENV strains 4 , 6 , 7 , 8 , 9 . Indeed, whilst there is certainly host and viral factor modulation of disease severity 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , the host immune landscape stands as the key risk determinant of a dengue infection’s clinical outcome 18 , 19 , 20 , 21 , 22 .

In high transmission intensity settings, most individuals experience more than one infection, thus making immune interactions between the cyclically dominant serotypes extremely relevant. Classical human challenge studies 19 , now replicated in non-human primates 23 , reveal transient protection from dengue disease and/or high viral load upon heterologous challenge in individuals primed with a specific viral serotype. What follows this short-lived heterologous immunity has been the focus of much scrutiny with a risk enhancement phenomenon emerging as a result of either antibody dependent enhancement 24 , 25 or immunopathogenesis akin to the original antigenic sin 26 , 27 . Exposure to a dengue infection induces a strong homologous immunity which was previously thought to be complete and lifelong 28 , but now understood to be only partial 29 , 30 and age dependent 21 , 31 . Subsequent exposure to a heterologous DENV serotype has been suggested to increase the risk of a clinical dengue outcome, resulting in higher rates of and dengue haemorrhagic fever in secondary infections 22 , 32 , 33 . Whilst some qualitative estimates of the generic strength and duration of cross-immunity have informed models fitted to epidemiological data 6 , 7 , 34 , it is still unclear whether pre-exposure to specific serotypes protects against or enhances the probability of illness upon subsequent infections with specific heterologous serotypes.

Longitudinal data in a high incidence setting where all 4 serotypes co-circulate would be ideal to understand how different immunity profiles modulate the clinical outcome of dengue infections. Several prospective cohort studies have provided valuable insight into immunity-related pathogenicity trends, decisively demonstrating that antibody dependent disease enhancing effects do occur in a non-serotype specific manner 35 , 36 , 37 , 38 , showing how the risk of clinical illness is modulated by a rapidly changing antibody repertoire 3 , identifying serological markers of secondary dengue infections for improved clinical management 39 , 40 , 41 , and suggesting a complex interaction between viral genetics and population dynamics of serotype-specific immunity in determining clinical outcomes 17 . However, no study has been able to disentangle serotype specific enhancement interactions, showing how pre-exposure antibody levels against a specific serotype modulate the likelihood of clinical illness with another serotype. A recent prospective cohort study of dengue infections in schoolchildren in Vietnam 42 collected detailed clinical and immunological data over the course of 6 years (2004–2009). The study reported 60% of infections to be secondary but found that the hospitalisation rate was similar for primary and secondary infections and the proportion of severe cases was similar in primary and secondary hospitalised cases. Cases were defined as primary or secondary given the acute sera IgM/IgG titre ratios, but used a threshold of 1.8 which was likely too large 39 , 40 , 43 . In that study, routine blood collection at the beginning of the year was also done for a sample of the cohort, allowing us to investigate two main issues here: (1) the serotype specific risk of clinical illness in individuals with different previous dengue virus exposures; (2) whether neutralizing antibody levels measured by the Plaque Reduction Neutralization Test (PRNT) would be a reliable serotype specific indicator of previous dengue exposure.

We then explore correlations between immunological baseline scenarios (using routinely collected sera) and future clinical outcomes, offering a comprehensive picture of dengue serotype interactions and highlighting how knowledge of the current antibody repertoire of an individual can help predict the severity of a potential future infection with the currently circulating serotype(s). This can be particularly important when considering deploying dengue vaccines. We also demonstrate how antibody titre differences between consecutive years can be used to accurately predict dengue asymptomatic infections, revealing the complex dynamical nature of the asymptomatic infection to clinical dengue case ratio.

Materials and Methods

Full details on the clinical study, methodology, assays used and data collection have been published in 42 . In summary, school aged children from a population of 249,535 inhabitants were enrolled into the study at three nursery schools, two primary schools, and one secondary school in southern Vietnam. This was a dynamic cohort with recruitment onto the lowest age group and replacement of drop-outs into the respective age classes. Enrolled children were actively and passively monitored year-round for febrile episodes. Absentees were visited at home by study nurses and children with an axillary temperature ≥38 °C were taken to the paediatric ward. During the school holiday trimester all children were visited at home three times a week. All hospitalisations were documented, whatever the reason. This study was approved by the scientific committee of the Pasteur Institute Ho Chi Minh City and by the Ministry of Health of Viet Nam. Written informed consent was obtained from the parents or legal representatives of all participants prior to enrolment. All experiments were performed in accordance with relevant guidelines and regulations.

Clinically-suspected dengue cases were defined as acute febrile illness events (reported by the adult caretaker or confirmed by axillary temperature ≥38 °C lasting over 2 days) for which a diagnosis of dengue or viral infection (i.e. acute fever without clinical signs of focused infection) was suspected. Two blood samples were collected for laboratory confirmation of each suspected dengue case: the first (acute sera) at consultation and the second (convalescent) either upon discharge of hospitalised cases or 10 days after outpatient consultation. Dengue infections were confirmed by one of the following virological assays: virus isolation, NS1 antigen assay and quantitative real-time polymerase chain reaction (qRT-PCR). Throughout this paper we refer to clinical dengue illness as symptomatic dengue infections with virological confirmation by virus isolation, NS1 or qRT-PCR assay and define asymptomatic infections as presumptive dengue infections without any apparent symptomatology.

Seroprevalence surveys were performed each December (low transmission season), at which time blood samples were collected from all enrolled children to assess the presence of antibodies (via ELISA), along with anthropometric and vital signs measurements. In a randomized subset of 200 subjects from the universe of enrolled children, serotype-specific quantification of the titre of neutralising antibodies (PRNT50) were performed. Due to this annual randomisation, consecutive PRNT50 titre measurements for the same individuals are infrequent. Sera from all dengue laboratory-confirmed cases were retrospectively analysed by PRNT50, thus providing a December snapshot of the antibody profiles of children later developing dengue illness. The total pool of analysed PRNT50 samples is then the aggregate set of random annual samples and all children that had confirmed dengue fever.

Statistical analyses

Due to the study design, individual serological follow-up was intermittent, with PRNT50 measurements restricted to annual surveys and clinical cases. The same individuals were not necessarily (and indeed infrequently) surveyed on consecutive years, thus we opted to analyse each person-year separately and investigate the variables affecting the risk of clinical dengue during each follow-up year. Only records for people with measured antibody titres and a known clinical endpoint at the end of the year were included.

We use the longitudinal data collected in 42 to address two main questions, each involving the use of different analytical techniques as discretised below: (i) how antibody titres measured at the beginning of each year modulate the serotype-specific risk of clinical illness and (ii) whether PRNT50 antibody titres can be used as a reliable serotype-specific indicator of previous dengue exposure.

How antibody titres modulate the serotype-specific risk of clinical illness

A baseline immunity effect was estimated by analysing the relative risk of clinical dengue illness in individuals with a different immune status (as quantified by PRNT50) at the beginning of each year (baseline). The relative risk of clinical dengue illness is the ratio between the clinical dengue illness rates in immune and naïve individuals, calculated as: OR = PI/PN, where PN and PI are the observed clinical dengue illness occurrence odds in naïve and immune individuals over each year, respectively. PI was calculated by dividing the number of clinical dengue illness cases (C) by the number of non-cases (NC) for each baseline immunity status. In a first instance we conservatively considered individuals with a PRNT50 titre below the detection threshold (<1/10 dil) to be immunologically naïve (this assumption is relaxed later) and consider the effects of serotype transcendent immunity (i.e. against any dengue serotype). We later calculated serotype-specific odds ratios clinical dengue illness, by accounting for serotype-specific cases in the numerator and excluding any case (i.e. caused by any serotype) from the denominator. For instance, the odds ratio of clinical dengue illness with serotype i was calculated by dividing the number of clinical dengue illness cases caused by serotype i by the number of non-cases (i.e. also excluding individuals infected with serotype j ≠ i ) for each baseline immunity status. For each reference serotype, PRNT50 titres were scanned and individuals were clustered into bins according to the measured homologous titre and the highest titre recorded among the heterologous serotypes. We used 6 bins, classifying titres into the following intervals: <10; 10–19; 20–39; 40–79; 80–159; ≥160. These intervals reflect the nature of the assay, where two-fold dilutions are performed until the number of plaque forming units is reduced by 50% compared to the serum free counterfactual. It is reported with a minimum value of 5 if no neutralisation occurs, 10 if one dilution is performed, 20 for two dilutions, and so on. If both measured homologous and heterologous titres fall in the first bin, the individual was considered fully naive. We then calculate the odds ratio of having clinical dengue illness with a specific serotype for PRNT50 titre bin k as:

where k = 1 represents fully naïve children. We used multinomial logistic regression to determine the association between the occurrence of clinical dengue illness and a set of independent variables describing the immunological status of each child including PRNT50 titres against DENV1–4 and IgG and IgM measurements (see Supplementary Table  S2 ), as well as ag, gender, and calendar year.

Several immunity descriptive summary variables were created to reflect the breadth of individual antibody profiles as summarised in Supplementary Table  S2 . We evaluated different models containing different combinations of predictors (Supplementary Table  S3 ) using the Akaike Information Criterion (AIC), which is defined as \(AIC=2{n}_{p}-2\,\mathrm{ln}(L)\) , where n p is the number of estimated parameters and L denotes the maximized likelihood. The predictive performance of each model was also assessed by calculating the area under the receiver operating characteristic (ROC) curve.

Multinomial logistic regression

Logistic regression methods are valuable tools to assess the effects of multiple explanatory predictors (numeric and/or categorical) on an outcome variable. A method of this kind was used to differentiate primary from secondary dengue infections, as defined by convalescent PRNT titres, using only acute serology results in 40 . When dealing with a polytomous outcome variable, one can use a natural extension of the binary logit model, the multinomial logistic model. It explains the relative risk of having a specific outcome versus a reference category, k , using a linear combination of p predictor variables. It can be written as:

where π i is the probability outcome i, J is the number of response categories (in this case, all possible clinical outcomes, including non-cases), α is the intercept, and p is the number of predictors. Labelling non-cases as the J th outcome category, we solve a total of 4 equations simultaneously (one for each serotype) to estimate the coefficients β . Assuming the coefficients for the non-cases to be zero, the probability of having dengue clinical illness with serotype j is given by:

The log likelihood of the multinomial logistic regression model can then be expressed as 44 , 45 :

where y ij contains the observed counts of the j th outcome variable in n i children. We use an iteratively weighted least squares algorithm available in the statistical toolbox of Matlab 2.14 to find the maximum likelihood estimates.

This framework provides an intuitive interpretation of the estimated coefficients. Taking coefficient β 11 as an example, it indicates how many times – exp( β 11 ) – the probability of a child having a clinical DENV1 illness increases for each unit increase in anti-DENV1 antibody titre (all else being constant). Negative coefficients thus reflect a decrease in likelihood of disease with increasing antibody titres. If we use a log2 transformation of the measured PRNT50 titres, the estimated coefficients β then reflect the relative probability of dengue illness for each additional log2 dilution.

The use of PRNT50 antibody titres as serotype-specific indicators of dengue exposure

We used machine learning techniques to analyse the occurrence of asymptomatic dengue infections. Similar techniques have been used recently to impute immunological status 46 and identifying subclinical infections 3 . Using a subset of our longitudinal data limited to individuals that had antibody titre measurements taken in two consecutive years, we trained a random forest algorithm (RFA) on individuals known to have been cases and those displaying no change or a decrease in antibody titres from one year to the next. This comprised a set of 363 individuals. We then used the resulting random forest model to predict the outcome of all others, i.e., children with an antibody rise (of any magnitude) for at least one serotype. It should be noted that the training set was comprised of clinical cases only, thus the predicted infections should have comparable antibody titre rises to those observed in clinical cases. A subset of the training data mentioned above was used to develop a serotype-specific RFA to predict the infecting serotype for the predicted non-clinical infections. Six un-typed clinical infections were not used to inform this RFA and were instead included in the subset of infections to predict. We can then easily calculate the proportion of children with sequential PRNT50 measurements which are predicted to have been infected by dividing the number of predicted asymptomatic infections by the number of individuals with sequential PRNT50 measurements. Assuming the remaining children in the population experience the same annual risk of exposure, we can extrapolate the number of expected sub-clinical infections in the whole study cohort. To calculate the asymptomatic infection to clinical case ratio we divide the number of predicted number asymptomatic infections in the whole cohort by the number of observed clinical dengue cases.

Random forest algorithm

The random forest algorithm (RFA) is an ensemble classifier with multiple low correlation decision trees aggregating into a low bias and low variance “forest”. Each tree in a random forest is trained on a bootstrap of the data, and each tree branch contains a random subset of all available variables. Final classification of each sample results from aggregating the votes of all trees in the forest. This algorithm has proven to be extremely accurate in classification tasks 47 , partly due to the embedding of the feature onto the model training process, and the integral usage of the training data (whereas other methods require a split into training and validation sets) 48 . Crucially, the classifier’s performance is evaluated on out-of-bag samples (samples left out of the bootstrapped data for each tree) in the form of a misclassification error. Variable importance is also estimated from the samples which are left out of the training set at each split of the tree, making the random forest algorithm very robust to over-fitting. In fact, random forests have been demonstrated not to over-fit as the number of trees grows to infinity, instead producing a limiting value of the prediction error 47 . We used the RandomForest R package to implement the RFA.

Epidemiological trends

Children were enrolled into the study from December 2003 until December 2006 as displayed in Table  1 , with the cohort size peaking in 2005 and the mean age consistently increasing as a consequence. No additional children were recruited in December 2007 and December 2008 in order to decrease the workload of the investigation team.

Incidence of dengue illness in the serology subset displayed a similar age profile for both genders (Supplementary Fig.  S1 ). An interesting serotype replacement pattern emerges, with DENV2 being progressively replaced by DENV1 (Supplementary Fig.  S1 ). Both DENV3 and DENV4 represent a much smaller proportion of all sampled viruses and do not exhibit any significant temporal trend.

PRNT50 titres as indicators of immune protection/enhancement

The distributions of PRNT50 titres against each serotype are skewed, with the bulk of individuals presenting with very low titres (58% of individuals having no detectable neutralizing antibodies and 70% presenting with PRNT50 < 20 against all serotypes). This means that standard boxplots would not be a good representation, thus we opted to display the density distributions of antibody titres through violin plots (Supplementary Fig.  S2 – right side panels). Pre-infection homologous antibody titres in individuals presenting with a clinical dengue illness caused by the same serotype are consistently low. Strikingly, individuals presenting with clinical dengue illness caused by DENV1 and DENV3 had similar antibody titre profiles, with high anti-DENV2 titres (means of 91.3 and 93.1 respectively), lower anti-DENV3 and anti-DENV4 titres, and very low to undetectable anti-DENV1 antibodies (means of 11.6 and 7.4 respectively). Also noteworthy are the high anti-DENV1 and anti-DENV2 antibodies (means of 146.9 and 85.8 respectively) found in DENV4 cases, as well as the high anti-DENV2 and anti-DENV4 antibodies in cases infected by DENV3 (means of 93.1 and 61.8 respectively). DENV1-infected cases had high anti-DENV2 levels (mean PRNT50 = 92), whereas DENV2 cases displayed the highest anti-DENV3 antibody titres (mean PRNT50 of 74.0).

Children with detectable neutralizing antibodies to any of the 4 serotypes were less likely to become clinically ill (regardless of infecting serotype) within the year following the blood sample, compared to completely naïve children (OR = 0.752 (0.577–0.979); p = 0.0346). Considering individuals with a PRNT50 titre over 80 against any serotype as immune leads to an even lower and more statistically significant relative risk (OR = 0.643(0.483–0.856); p = 0.0025) (Supplementary Table  S1 ). Discretising immune profiles further, we classified children into immunity level categories for each serotype, according to their measured titre for both homologous and heterologous titres (Table  2 ). Children with a combination of low homologous titres (PRNT50 < 40) and intermediate-to-high heterologous titres (PRNT50 ≥ 40) have increased odds of having a dengue clinical episode relative to fully naïve individuals. Conversely, immune individuals to both homologous and heterologous serotypes (PRNT50 > 40) are protected against disease.

Cross-serotype interactions

To disentangle the interactions between antibody titre measurements and other factors such as age and gender in determining the likelihood of a given clinical outcome, we undertook an exhaustive multinomial model selection process that explored the predictive power of several covariates (Tables  S2 , S3 ). Ultimately, the most parsimonious model (as per AIC) that accurately fits the observed dengue clinical outcomes is one informed on baseline PRNT50 titres against each of the serotypes, age and year of sample collection (see Supplementary Table  S4 ). Summary measures of immunity describing the richness of the immune profile (such as dominance or skewedness) and demographic indices (age, gender) do not improve the model fit significantly. The estimated coefficients obtained with model 49 are shown in Table  3 . As expected, estimated homologous serotype coefficients are negative in all models, meaning having higher titres against one serotype decreases the odds of having dengue illness with that same serotype, although this effect is only significant for DENV1 and DENV2. The homologous antibody effects in DENV3 and DENV4 displayed the largest negative coefficients, suggesting a strong protective effect, but were ultimately not statistically significant due to the small number of cases infected with those serotypes. A detailed exploration of the homologous titres protective effect is given in Supplementary Table  S9 .

We also uncover a series of cross-serotype interactions manifested in the risk of acquisition of dengue illness as follows:

Clinical DENV1 illness: no significant effect of PRNT50 titres against any of the other serotypes on the odds of clinical DENV1 illness detected.

Clinical DENV2 illness: we found significantly increased odds of clinical DENV2 illness in children with high titres against DENV1. Supplementary Fig.  S2 shows that several children with high antibody titres against DENV1 at the time of the annual sero-surveys succumbed to DENV2 or DENV4 illness (top right panel).

Clinical DENV3 illness: we found that elevated titres against DENV1 confers protection against clinical DENV3 illness and that the presence of anti-DENV2 or anti-DENV4 titres significantly enhance the odds of clinical DENV3 illness.

Clinical DENV4 illness: high anti-DENV1 titres increase the odds of clinical DENV4 illness.

The odds ratio of clinical case illness in children with low antibody titres (PRNT50 < 40) to a specific serotype, conditional on different PRNT50 thresholds for the other serotypes (serving as indicators of previous exposure) can be found in Fig.  1 . These results reinforce the serotype-specific interactions described above but also demonstrate that even low titres can have a disease enhancing effect and highlight the non-linear relationship nature of serotype interactions. We have highlighted in red, the serotype interactions identified as significant in the multinomial logistic model in Fig.  1 and observe how the odds ratios of clinical disease are modulated by imposing different PRNT50 cut-offs for heterologous immunity. The classification that considers PRNT50 = 40 as the homologous immunity threshold for both homologous and heterologous titres is the most consistent with the multinomial logistic regression. We present the Odds Ratios for different titre cut-off values in Supplementary Fig.  S4 .

Odds ratio of dengue illness in the year following neutralising antibody titre measurements. The odds ratio presented here refers to children with a homologous PRNT50 titre under 40, i.e., non-immune to the reference dengue serotype thus reflecting the ratio between the odds of having clinical dengue illness when immune to heterologous serotypes (conditional on having a PRNT50 < 40 to the homologous serotype) and the odds of becoming ill in the absence of immunity to any serotype.

The overall best fitting model reveals a positive age dependence on the odds of developing clinical dengue DENV2 illness, suggesting older children are at higher risk of DENV2 disease. Even more significant is the effect of calendar year, which clearly shows a temporal increase in the odds of DENV2 illness along with a decrease in DENV1 clinical case odds. This is in line with the observed serotype replacement pattern observed in Figs  2 and S1 .

Evaluation of the asymptomatic infection prediction model. The violin plots in the top two rows display the distribution of the mean rise in titres (across all serotypes) in consecutive years for predicted infections and predicted non-infections compared to the observed cases. The bottom row shows the time series of predicted infections by serotype (right) compared to the observed dengue clinical case time series (left).

The best fitting model including IgG and IgM as covariates (model 87) suggest that elevated IgG titres are disease enhancing (positive coefficients), whereas increased IGM titres do not seem to affect the likelihood of having dengue illness (coefficient are very close to zero).

Noteworthy is the inclusion of a covariate on the breadth of immune repertoire in the logistic model with the highest log-likelihood (but second highest AIC). This covariate is a binomial response variable which indicates whether there are at least two measured PRNT50 titres over 40 per sample. Interestingly, the estimated coefficients suggest a difference between having a raised antibody against a single serotype compared to having a broader antibody repertoire, with no enhancement in the latter but rather a cross-protection effect. Considering antibody repertoires with multiple PRNT50 titres over 80 does not improve the fit. We investigate this relationship further by calculating the Odds Ratios of clinical disease given combinations of homologous and heterologous PRNT50 titres, much like in Fig.  1 . The results (Supplementary Fig.  S3 ) indicate that, in this study, disease enhancement is more likely in children with pre-existing elevated antibody titres against a single serotype.

PRNT50 titres as indicators of asymptomatic infections

Using our longitudinal dataset, we implemented a random forest algorithm (RFA) to predict the likely outcomes in individuals whose antibody titres (to any of the serotypes) rose between any two consecutive years. The non-serotype specific RFA trained on individuals with dropping or unchanged titres together with those that were clinical cases had a predictive error of 0.55%, only misclassifying 2 in 363 data entries. A total of 37 asymptomatic dengue infections were predicted to have occurred in the 109 children displaying some immunity boost. The antibody rises observed in these children are similar to those observed in clinical cases, and markedly different from the ones observed in individuals predicted to not have been infected (Fig.  2 ). The serotype specific RFA performed similarly well, with a 1.4% prediction error, although it was unable to discriminate infections with DENV3 and DENV4, due to the very low number of cases with these serotypes in the training set (2 and 1 respectively). DENV1 and DENV2 cases were accurately predicted in 6 out of 7 and 7 out of 8 children. Also, 4 out of 5 untyped clinical cases were predicted to be DENV2 infections, whereas the remaining case showed no antibody rise in titres in the year following illness and was thus predicted to not have been the result of a dengue infection. The time-varying serotype-specific incidence of predicted infections (comprising a set of the 4 untyped clinical cases and 29 asymptomatic infections) displays the same DENV2 to DENV1 serotype replacement pattern seen in clinical cases (bottom right panel in Fig.  2 ).

Estimation of these asymptomatic infections in a small subset of individuals with sequential PRNT50 measurements allowed us to extrapolate the proportion of infected individuals in the whole cohort and to thus get an estimate for the total number of sub-clinical infections in the population and ultimately the asymptomatic infection to clinical case ratio, which shows substantial fluctuation over time (Supplementary Fig.  S5 ).

Dengue pathogenesis is extremely complex. Following a dengue infection, individuals enter a cross-serotype immunity period of unknown duration followed by life-long immunity from homologous challenges along with what can only be described as a controversial and multi-factorial heterologous risk enhancement. Here we show that baseline immunity to any serotype (defined as having any detectable titre) offers a substantive reduction in dengue illness risk against any serotype (RR = 0.81 [0.67–0.99]) while higher titres offer an increased benefit (Supplementary Table  S1 ). Indeed, there has been some evidence in the literature for heterologous neutralization with antibodies targeting DENV protein epitopes that are shared among serotypes 3 , 49 .

Given our knowledge of the immune profile of children at the start of a given year and of their clinical manifestations throughout the year, we have partitioned our population into a range of immune subgroups defined by their PRNT50 titres. For each serotype, the subgroup with undetectable titres to any serotype was defined as the control group and odds ratios of dengue illness were calculated for each other subgroup (Table  2 ). We found that the odds of clinical occurrence are significantly enhanced in children with low-to-intermediate (PRNT50 < 40) homologous titres combined with intermediate to high (PRNT50 > 40) heterologous titres, consistent with reported antibody dependent enhancement effects 22 , 32 , 33 , 38 . These results are observed across all serotypes but not as significant for DENV1, which shows an exceedingly competent homologous neutralizing potential, with titres over 40 inducing protection regardless of the heterologous context. Lower protective neutralising titres for DENV1 compared to other serotypes were also described in 50 . For all serotypes, high antibody titres to the homologous and at least one of the heterologous serotypes induce clinical protection upon infection with any serotype. Due to the low numbers of individuals in some of the subgroups (see Tables  S5 – S8 ), many relative risks are not statistically significant. However, the observed trends are consistent across all serotypes. We must stress that lack of significance does not necessarily imply a relationship does not exist as there might be insufficient statistical power in the data and to ascertain any serotype interaction. The numbers in the top left corner of cells in Table  2 indicates the subset of PRNT50 titre bins where a statistically significant interaction could potentially be detected (mostly limited to low homologous titres) – in this case, those with a grade of evidence equal to 3. The odds ratio for DENV2 (38.06) albeit statistically significant should be carefully interpreted, as it results from a very small number of cases. Both viral neutralization and ADE effects have been associated with the number of antibodies bound to the virion 51 , 52 . ADE has been extensively studied in vitro and occurs when antibody levels are lower than the threshold for neutralization, as long as there is sufficient number of antibodies to support stable attachment of the virion to cells 53 . Here we further characterise this hypothesis, showing an enhancement effect for homologous antibody titres under the protective threshold (here found to be PRNT50 = 40) and heterologous antibody titres over said threshold. These results are evident when exploring the odds ratios for different PRNT titre cut-offs to define immunity status as shown in Fig.  1 , and fit with the non-linearity previously shown in 3 , 38 . These studies established that pre-existing antibody titres against any serotype are key in determining disease risk and what shape that risk regulating immunity function takes. Whilst Salje et al . 3 show the existence of a post infection stable antibody setpoint of 1 year, after which a PRNT titre threshold of 40 is deemed to be protective, Katzelnik and colleagues 38 clearly demonstrate a serotype non-specific ADE effect in humans. Here, we retrieve both results and add a critical component to that narrative by identifying serotype-specific pairs that are linked to increased clinical dengue risk.

We must stress that in this study we can only correlate clinical outcomes with measured PRNT50 titres from sera collected in the 12 months prior to clinical illness, thus operating on a short time scale and blinded to long term antibody titre dynamics. The one year setpoint followed by exponential decay suggested in 3 offers assurances that high antibody titres are a reflection of recent infections, thus validating our time frame. We cannot, however, make inferences on the cumulative nature of exposure. The data analysed in this study also contain a small subset of children which were followed up for 2 years or more, allowing for a dengue disease outcome prediction model to be constructed. We used this subset of children for which we have measured PRNT50 titres in consecutive years as training data for a random forest algorithm that predicts putative clinical outcomes. We developed both a serotype-specific and non-specific version of this algorithm reaching a better predictive performance than standard multinomial logistic regression models for prediction of the infecting dengue serotypes 54 . Out of 217 individuals (some of which with multiple data entries) 24 children fell ill during the follow up period. Our RFA proposes 37 more infections (33 for which the infecting serotype is predicted as well) to have occurred, resulting in an apparent to symptomatic case rate ranging from 1.88 to 11.72 in accordance with has been described for other trials sites in SE Asia 22 , 55 , 56 , and predicted by a similar method 3 .

These results paint a picture of extremely complex cross-serotype interactions underpinning dengue epidemiology. Multinomial models can help disentangle some of these properties and generalise cross-serotype interactions, possibly shedding some light on the relevance of particular combinations of sequential infections. Our multinomial logistic regression model offers a moderate predictive power as evidenced by the AUC values in Supplementary Table  S4 . This is not surprising given that this was not a controlled challenge study and an unknown subset of the non-cases was likely not exposed to any dengue virus. The purpose of the multinomial logistic model is to explore how the immunity landscape of the population affects the probability of specific outcomes, thus unveiling cross-serotype interactions. It does so to great effect, showing clear signals of increased risk of clinical DENV2 illness due to elevated anti-DENV1 antibodies and to a lesser extent by increased IgG levels. High anti-DENV1 titres also seem to increase the occurrence of DENV4 cases and decrease the chances of DENV3 illness. Indeed, the sequences of infections which we find to translate into a higher risk of clinical dengue illness upon secondary infection are: DENV1 followed by DENV2, DENV1 followed by DENV4, DENV2 followed by DENV3 and DENV4 followed by DENV3. Some of these sequences have been fairly well documented in other settings, particularly the increased risk of DENV2 following DENV1 infection 32 , 37 , 57 . Plotting titre data as a function of the resulting clinical dengue serotype (Supplementary Fig.  S2 ) clearly illustrates that a considerable number of children falling ill with DENV2 or DENV4 previously had high titres to DENV1. Conversely, low anti-DENV1 titres are found in individuals latter succumbing to DENV1 or DENV3 illness.

Phylogenetics of the dengue virus suggests that it clusters into two genetic clusters: one with DENV1 and DENV3, and another containing DENV2 and DENV4 58 . This genetic clustering seems to have a direct translation to an antigenic relationship, with DENV1 and DENV3 displaying significant cross-protection, with anti-DENV antibodies raised against one of these viruses suggested to protect against disease caused by the other (Fig.  1 and Table  3 ). Strikingly, in this study we find risk enhancement interactions exclusively between serotypes in different genetic clusters. The absence of a significant DENV1 enhancement by DENV2 antibodies is also striking in the context of the observed serotype replacement dynamics in Vietnam during this period (Fig.  2 ) and suggests that the DENV2 replacement by DENV1 was not driven by antibody dependent enhancement but was rather the result of an epidemiological context characterised by a generalised lack of immunity to DENV1.

Although throughout this study we have only made links between humoral immunity and the risk of dengue clinical illness, the role of other factors, namely that of cellular mediated immunity, cannot be understated. Whilst antibody responses, when taken in isolation from other components of the immune system, can modulate the severity of in vivo infections, the presence of cellular immunity can nullify any enhancement effect 59 , or on the contrary contribute to severe disease 27 . Also in murine models, it has been reported that lethal antibody enhancement of dengue disease can be prevented by Fc modification 60 . More recently, severe dengue illness was explained by a substantial production of IgGs with enhanced affinity for the activating Fc receptor FcγRIIIA 61 , whilst another study found higher dengue IgG levels in symptomatic infections compared to asymptomatic ones 62 . Thus, the coefficients retrieved for IgG here might be an indication that children displaying increased IgG tires had high affinity IgGs. In this study we report serotype specific interactions leading to dengue illness enhancement, particularly highlighting sequences of infections (conditional on certain PRNT50 titre thresholds being met) with different serotypes which lead to a statistically significant increase in disease risk. We also reinforce the potential role of IgGs in inducing dengue illness. The results presented are a mere reflection of the observable phenomenon of enhancement and its association with pre-infection antibody titres and not a mechanistic or causal explanation of the role played by antibodies in the disease enhancement effect.

This study further highlights the extreme complexity of dengue pathogenesis. It uncovers disease enhancement effects across specific serotype pairs, suggesting the most likely sequences of infection in dengue secondary clinical cases. Whilst we appreciate that the implementation of serological screening cannot be performed routinely in large populations can be challenging, our results offer some guidance as to how severe future epidemics could potentially be, given the serotype replacement history in an epidemiological setting. Furthermore, our results suggest that vaccines that confer broadly neutralizing antibody responses could alleviate enhancement related concerns, something that became clear from the CYD-TDV vaccine efficacy analyses 46 .

Data Availability

Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi’s data sharing criteria, eligible studies, and process for requesting access can be found at: https://www.clinicalstudydatarequest.com.

Brady, O. J. et al . Refining the Global Spatial Limits of Dengue Virus Transmission by Evidence-Based Consensus. PLoS Negl. Trop. Dis. 6 , e1760 (2012).

Article   Google Scholar  

Bhatt, S. et al . The global distribution and burden of dengue. Nature 496 , 504–7 (2013).

Article   ADS   CAS   Google Scholar  

Salje, H. et al . Reconstruction of antibody dynamics and infection histories to evaluate dengue risk. Nature 557 , 719–723 (2018).

Recker, M. et al . Immunological serotype interactions and their effect on the epidemiological pattern of dengue. Proc. R. Soc. B Biol. Sci. 276 , 2541–2548 (2009).

Nisalak, A. et al . Serotype-specific dengue virus circulation and dengue disease in Bangkok, Thailand from 1973 to 1999. Am. J. Trop. Med. Hyg. 68 , 191–202 (2003).

Wearing, H. J. & Rohani, P. Ecological and immunological determinants of dengue epidemics. Proc. Natl. Acad. Sci. 103 , 11802–11807 (2006).

Adams, B. et al . Cross-protective immunity can account for the alternating epidemic pattern of dengue virus serotypes circulating in Bangkok. Proc. Natl. Acad. Sci. 103 , 14234–14239 (2006).

Adams, B. & Boots, M. Modelling the relationship between antibody-dependent enhancement and immunological distance with application to dengue. J. Theor. Biol. 242 , 337–346 (2006).

Article   MathSciNet   CAS   Google Scholar  

Ferguson, N. M., Donnelly, C. A. & Anderson, R. M. Transmission dynamics and epidemiology of dengue: insights from age-stratified sero-prevalence surveys. Philos. Trans. R. Soc. B Biol. Sci. 354 , 757–768 (1999).

Article   CAS   Google Scholar  

Stephens, H. A. F. et al . HLA-A and -B allele associations with secondary dengue virus infections correlate with disease severity and the infecting viral serotype in ethnic Thais. Tissue Antigens 60 , 309–18 (2002).

Sakuntabhai, A. et al . A variant in the CD209 promoter is associated with severity of dengue disease. Nat. Genet. 37 , 507–513 (2005).

Nguyen, T. H. et al . Association between sex, nutritional status, severity of dengue hemorrhagic fever, and immune status in infants with dengue hemorrhagic fever. Am. J. Trop. Med. Hyg. 72 , 370–4 (2005).

Rico-Hesse, R. et al . Molecular evolution of dengue type 2 virus in Thailand. Am. J. Trop. Med. Hyg. 58 , 96–101 (1998).

Leitmeyer, K. C. et al . Dengue virus structural differences that correlate with pathogenesis. J. Virol. 73 , 4738–47 (1999).

CAS   PubMed   PubMed Central   Google Scholar  

Bennett, S. N. et al . Selection-Driven Evolution of Emergent Dengue Virus. Mol. Biol. Evol. 20 , 1650–1658 (2003).

Balmaseda, A. et al . Serotype-specific differences in clinical manifestations of dengue. Am. J. Trop. Med. Hyg. 74 , 449–56 (2006).

OhAinle, M. et al . Dynamics of Dengue Disease Severity Determined by the Interplay Between Viral Genetics and Serotype-Specific Immunity. Sci. Transl. Med. 3 , 114ra128–114ra128 (2011).

Alvarez, M. et al . Dengue hemorrhagic Fever caused by sequential dengue 1-3 virus infections over a long time interval: Havana epidemic, 2001-2002. Am. J. Trop. Med. Hyg. 75 , 1113–7 (2006).

SABIN, A. B. Research on dengue during World War II. Am. J. Trop. Med. Hyg. 1 , 30–50 (1952).

Halstead, S. B. Neutralization and antibody-dependent enhancement of dengue viruses. Adv. Virus Res. 60 , 421–67 (2003).

Guzmán, M. G. et al . Effect of age on outcome of secondary dengue 2 infections. Int. J. Infect. Dis. 6 , 118–24 (2002).

Burke, D. S., Nisalak, A., Johnson, D. E. & Scott, R. M. A prospective study of dengue infections in Bangkok. Am. J. Trop. Med. Hyg. 38 , 172–80 (1988).

Kochel, T. J. et al . Cross‐Serotype Neutralization of Dengue Virus in Aotus nancymae Monkeys. J. Infect. Dis. 191 , 1000–1004 (2005).

Boonnak, K. et al . Role of Dendritic Cells in Antibody-Dependent Enhancement of Dengue Virus Infection. J. Virol. 82 , 3939–3951 (2008).

Halstead, S. B. & O’Rourke, E. J. Dengue viruses and mononuclear phagocytes. I. Infection enhancement by non-neutralizing antibody. J. Exp. Med. 146 , 201–17 (1977).

Rothman, A. L. Dengue: defining protective versus pathologic immunity. J. Clin. Invest. 113 , 946–951 (2004).

Rothman, A. L. Immunity to dengue virus: a tale of original antigenic sin and tropical cytokine storms. Nat. Rev. Immunol. 11 , 532–543 (2011).

Gibbons, R. V. et al . Analysis of repeat hospital admissions for dengue to estimate the frequency of third or fourth dengue infections resulting in admissions and dengue hemorrhagic fever, and serotype sequences. Am. J. Trop. Med. Hyg. 77 , 910–3 (2007).

Waggoner, J. J. et al . Homotypic Dengue Virus Reinfections in Nicaraguan Children. J. Infect. Dis. 214 , 986–993 (2016).

Forshey, B. M. et al . Incomplete Protection against Dengue Virus Type 2 Re-infection in Peru. 1–17, https://doi.org/10.1371/journal.pntd.0004398 (2016).

Cummings, D. A. T. et al . The Impact of the Demographic Transition on Dengue in Thailand: Insights from a Statistical Analysis and Mathematical Modeling. PLoS Med. 6 , e1000139 (2009).

Sangkawibha, N. et al . Risk factors in dengue shock syndrome: a prospective epidemiologic study in Rayong, Thailand. I. The 1980 outbreak. Am. J. Epidemiol. 120 , 653–69 (1984).

Halstead, S. B., Nimmannitya, S. & Cohen, S. N. Observations related to pathogenesis of dengue hemorrhagic fever. IV. Relation of disease severity to antibody response and virus recovered. Yale J. Biol. Med. 42 , 311–28 (1970).

Nagao, Y. & Koelle, K. Decreases in dengue transmission may act to increase the incidence of dengue hemorrhagic fever. Proc. Natl. Acad. Sci. 105 , 2238–2243 (2008).

Libraty, D. H. et al . A Prospective Nested Case-Control Study of Dengue in Infants: Rethinking and Refining the Antibody-Dependent Enhancement Dengue Hemorrhagic Fever Model. PLoS Med. 6 , e1000171 (2009).

Graham, R. R. et al . A prospective seroepidemiologic study on dengue in children four to nine years of age in Yogyakarta, Indonesia I. studies in 1995-1996. Am. J. Trop. Med. Hyg. 61 , 412–9 (1999).

Endy, T. P. et al . Relationship of Preexisting Dengue Virus (DV) Neutralizing Antibody Levels to Viremia and Severity of Disease in a Prospective Cohort Study of DV Infection in Thailand. J. Infect. Dis. 189 , 990–1000 (2004).

Katzelnick, L. C. et al . Antibody-dependent enhancement of severe dengue disease in humans. Science (80-.). 358 , 929–932 (2017).

Changal, K. H. et al . Differentiating secondary from primary dengue using IgG to IgM ratio in early dengue: an observational hospital based clinico-serological study from North India, https://doi.org/10.1186/s12879-016-2053-6 .

Hanh Tien Nguyen, T. et al . Methods to discriminate primary from secondary dengue during acute symptomatic infection, https://doi.org/10.1186/s12879-018-3274-7 .

Jayathilaka, D. et al . Role of NS1 antibodies in the pathogenesis of acute secondary dengue infection, https://doi.org/10.1038/s41467-018-07667-z .

Tien, N. T. K. et al . A prospective cohort study of dengue infection in schoolchildren in Long Xuyen, Viet Nam. Trans. R. Soc. Trop. Med. Hyg. 104 , 592–600 (2010).

Khurram, M. et al . Dengue hemorrhagic fever: Comparison of patients with primary and secondary infections. J. Infect. Public Health 7 , 489–495 (2014).

Czepiel, S. A. Maximum Likelihood Estimation of Logistic Regression Models: Theory and Implementation ., https://czep.net/stat/mlelr.pdf  (2002).

Davidson, R. & MacKinnon, J. G. Econometric theory and methods . (Oxford University Press, 2009).

Dorigatti, I. et al . Refined efficacy estimates of the Sanofi Pasteur dengue vaccine CYD-TDV using machine learning. Nat. Commun. 9 , 3644 (2018).

Breiman, L. Random Forests. Mach. Learn. 45 , 5–32 (2001).

Saeys, Y., Inza, I. & Larranaga, P. A review of feature selection techniques in bioinformatics. Bioinformatics 23 , 2507–2517 (2007).

Lai, C.-Y. et al . Antibodies to envelope glycoprotein of dengue virus during the natural course of infection are predominantly cross-reactive and recognize epitopes containing highly conserved residues at the fusion loop of domain II. J. Virol. 82 , 6631–43 (2008).

Buddhari, D. et al . Dengue virus neutralizing antibody levels associated with protection from infection in thai cluster studies. PLoS Negl. Trop. Dis. 8 , e3230 (2014).

Morens, D. M., Halstead, S. B. & Marchette, N. J. Profiles of antibody-dependent enhancement of dengue virus type 2 infection. Microb. Pathog. 3 , 231–237 (1987).

Pierson, T. C. et al . The stoichiometry of antibody-mediated neutralization and enhancement of West Nile virus infection. Cell Host Microbe 1 , 135–45 (2007).

Dowd, K. A. & Pierson, T. C. Antibody-mediated neutralization of flaviviruses: a reductionist view. Virology 411 , 306–15 (2011).

van Panhuis, W. G. et al . Inferring the Serotype Associated with Dengue Virus Infections on the Basis of Pre‐ and Postinfection Neutralizing Antibody Titers. J. Infect. Dis. 202 , 1002–1010 (2010).

Endy, T. P. et al . Determinants of Inapparent and Symptomatic Dengue Infection in a Prospective Study of Primary School Children in Kamphaeng Phet, Thailand. PLoS Negl. Trop. Dis. 5 , e975 (2011).

Endy, T. P. et al . Epidemiology of inapparent and symptomatic acute dengue virus infection: a prospective study of primary school children in Kamphaeng Phet, Thailand. Am. J. Epidemiol. 156 , 40–51 (2002).

Guzmán, M. G. et al . Epidemiologic studies on Dengue in Santiago de Cuba, 1997. Am. J. Epidemiol . 152 , 793–9; discussion 804 (2000).

Weaver, S. C. & Vasilakis, N. Molecular evolution of dengue viruses: Contributions of phylogenetics to understanding the history and epidemiology of the preeminent arboviral disease. Infect. Genet. Evol. 9 , 523–540 (2009).

Zellweger, R. M. et al . Role of humoral versus cellular responses induced by a protective dengue vaccine candidate. PLoS Pathog. 9 , e1003723 (2013).

Balsitis, S. J. et al . Lethal Antibody Enhancement of Dengue Disease in Mice Is Prevented by Fc Modification. PLoS Pathog. 6 , e1000790 (2010).

Wang, T. T. et al . IgG antibodies to dengue enhanced for FcγRIIIA binding determine disease severity. Science (80-.). 355 , 395–398 (2017).

Luo, S. et al . Seroprevalence of dengue IgG antibodies in symptomatic and asymptomatic individuals three years after an outbreak in Zhejiang Province, China. BMC Infect. Dis. 18 , 92 (2018).

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R.A. developed the methodology, performed the analysis, and wrote the manuscript. I.D. processed the data and helped draft the manuscript. L.C. shared the raw data and oversaw the data analysis. C.L. designed the clinical study and collected the data. N.F. supervised the analyses. All authors discussed the results and reviewed the manuscript.

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Aguas, R., Dorigatti, I., Coudeville, L. et al. Cross-serotype interactions and disease outcome prediction of dengue infections in Vietnam. Sci Rep 9 , 9395 (2019). https://doi.org/10.1038/s41598-019-45816-6

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• Case report
• Open access
• Published: 18 December 2018

Series of 10 dengue fever cases with unusual presentations and complications in Sri Lanka: a single centre experience in 2016

• S. A. M. Kularatne 1 ,
• Udaya Ralapanawa   ORCID: orcid.org/0000-0002-7416-7984 1 ,
• Chamara Dalugama 1 ,
• Jayanika Jayasinghe 1 ,
• Sawandika Rupasinghe 1 &
• Prabashini Kumarihamy 2  

BMC Infectious Diseases volume  18 , Article number:  674 ( 2018 ) Cite this article

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Dengue has global importance as a dreaded arboviral infection. It has 4 serotypes of epidemiological imporatnce. The classification denotes two clinical spectrums- dengue fever (DF) and dengue haemorragic fever (DHF). Most cases are stereotype and amenable to fluid resuscitation. However, unusual manifestations cause fatalities and often overlooked. This study describes 10 such dengue cases to fill the knowledge gaps.

Case presentation

All 10 patients presented to the Teaching Hospital, Peradeniya, Sri Lanka during mid-year epidemic of dengue in 2016. The mean age is 27 years (range 12-51 years) comprising 6 females and 4 males. The group had 7 DHF, 3 DF and 2 primary dengue infections who predominantly had severe bleeding into gut. Other potentially life threatening problems were acute severe hepatitis, severe septic shock, myocarditis, erratic rapid plasma leak, intracranial bleeding, diarrhoea and decompenstaed dengue shock due to 3rd space fluid leak. Blood transfusions and other empirical therapeutic methods were used apart from meticulous fluid management to suit issues of each patient. Bedside ultrasound scanning helped early detection of critical phase. All recovered fully.

Conclusions

Dengue is an extremely challenging infection to treat in the globe today. Above unusual presentation and complications could be fatal, if not detected early where therapeutic window period is very short. Clinicians need awareness of these problems which are not uncommon, but underreported and often overlooked. The clinical management of each patient was described for the purpose sharing the experiences.

Peer Review reports

Dengue is the most common arboviral infection in the Southeast Asia. Dengue virus has four related but antigenically distinct serotypes: DENV-1, DENV-2, DENV-3, and DENV-4 [ 1 ]. The global burden of dengue has increased in recent decades causing huge impact on both human health and the national economics [ 1 , 2 , 3 ] . Dengue infection has a diverse clinical presentation ranging from asymptomatic subclinical infection to severe multi-organ involvement [ 3 ]. Although, vascular plasma leak is the commonest manifestation, dengue can manifest in multitude of unusual presentations due to organ dysfunction that can carry high mortality [ 2 , 3 ]. Early detection of such manifestations and prompt action could avert the adverse outcome where clinicians need knowledge and experience. Aim of this case series is to present 10 such unusual dengue cases managed in a single hospital over 1 year period. These patients presented to Teaching Hospital, Peradeniya (THP), Sri Lanka in 2016 and recovered fully following problem based tailored management.

Case 1: (erratic rapid plasma leak during early critical phase)

A 22-year-old female admitted to THP with a one-day history of fever proceeded by frontal headache of 3 days. On admission, she had arthralgia, myalgia, mild postural dizziness and nausea. She has passed urine normal amount. She was hemodynamically stable with a blood pressure of 96/64 mmHg without a postural drop. Abdomen was soft and non-tender. Clinically, she did not have evidence of plasma leak. Her blood test was positive for dengue NS1 antigen. On 3rd day of fever, ultra sound scan of abdomen detected thin rim of free fluid in the hepato-renal pouch and moderate gall bladder wall oedema with mild pericholycystic fluid. She did not have pleural effusion or ascites. Neither she had postural drop of blood pressure, tachycardia or right hypochondrial tenderness. However, her haematocrit has risen from 33 to 38%. In a flash, within the next 6 h, she developed significant ascites (moderate) and bilateral moderate pleural effusions with a reduction of urine output. She had fluctuation of urine output and blood pressure and required several normal saline boluses and Dextran-40 along with frusemide to maintain vital parameters. Sixty percent of her calculated fluid quota was utilized in the 1st 12 h of tentative critical phase. Her clinical status gradually improved within the next 3 days. But, there was delayed resolution of effusion and ascites. Her serum albumin level dropped during the critical phase and took days reverse. Her recovery was uneventful and discharged on day 6 of the hospital stay. She had erratic rapid leaking of plasma into serous cavities during critical phase.

Case 2: (severe hepatitis with increased transaminases and gross ascites after critical phase)

A previously healthy 39-year-old female, admitted to the THP with a history of fever for 4 days. She had nausea, vomiting, arthralgia, myalgia and headache. She did not have any bleeding manifestations or abdominal pain. On examination, she had mild dehydration with low volume pulse. Blood pressure was 100/80 mmHg in supine position and 90/80 mmHg on standing. Right lung base was stony dull on percussion and had absent breath sounds. Ultrasound scan revealed a right sided plural effusion with free fluid in the abdomen. The patient was managed as critical phase of dengue haemorrhagic fever (DHF) with meticulous titration of fluids according to the haematocrit values. She remained hemodynamically stable with a stable haematocrit values during the critical phase. On day 7 of illness, dengue serology showed positive IgM and IgG titers. After completion of critical phase on 7th day of the illness, she complained of abdominal pain and back pain. Clinical examination found s mild icterus and tense ascites. Laboratory investigations revealed a marked rise in liver enzyme levels (ALT 204 to 1391 u/L and AST 505 to 4519 u/L) with an INR of 1.9. Diagnosis of acute hepatitis leading into acute liver failure was made and viral hepatitis was excluded by doing hepatitis A IgM, hepatitis B surface antigen and hepatitis C IgM which were negative. She denied self-medication with high doses of paracetamol. Further, she was treated with intravenous N acetyl cysteine 150 mg/hour infusion as an empirical treatment. Her low albumin level was corrected with intravenous human albumin administration. Antibiotics including oral metronidazole and intravenous ceftriaxone was administered at the same time to cover bacterial infections. She was given intravenous vitamin K for 3 days to prevent clotting factor depletion whilst monitoring liver transaminases and clotting parameters. Finally she was discharged on 12th day of the illness with near normal liver transaminases and normal clotting profile without residual free fluids in her abdomen. Further follow of after 21 days revealed completely normal liver biochemistry.

Case 3: (DEN 2, intracranial Haemorrhage in DHF)

A19- year-old male, previously healthy university student admitted to THP having a febrile illness with arthralgia and myalgia for 5 days duration. On the way to the hospital, the patient had postural dizziness and fainting attack causing impact on the forehead. Soon after admission, he developed a generalized tonic-clonic seizure which lasted for 5 min with post ictal drowsiness. On examination, he was not pale but had conjunctival hemorrhages. He had a contusion over the forehead due to fall. He was hemodynamically stable with a blood pressure of 126/90 mmHg and a pulse rate of 92 beats per minute without clinical evidence of plasma leaking. Ultrasound scan revealed a thin rim of free fluid in the abdomen. Dengue NS 1 antigen and Dengue Ig M and IgG both were positive. Serotype of dengue was identified as DEN 2. Diagnosis of DHF entering into critical phase was made and commenced intense monitoring with administration of intravenous and oral fluid according to guidelines, Meanwhile, the patient was found to be drowsy but arousable without having any lateralizing neurological deficits. Both optic fundi were normal. Non-contrast CT brain revealed bilateral frontal lobe hyperdense areas with mild cerebral oedema with minimal midline shift, suggestive of intra-cranial hemorrhages. His clotting parameters were within the normal limits. He was transfused with platelets to keep the platelet count more than 50 × 10 6 /L and managed conservatively with adequate intravenous fluids, intravenous antibiotics and antiepileptic drugs. He was started on intravenous phenytoin sodium and later converted to oral phenytoin. Cerebral oedema was managed with intravenous dexamethasone and intravenous mannitol. He was administered with intravenous tranexamic acid to retard further bleeding. Critical phase was uneventful. His headache and drowsiness improved over the next 5 days and discharged with oral antiepileptics.

Case 4: (DEN 1 causing myocarditis and DHF together)

A-17-year-old previously healthy female presented to THP with a history of fever for 2 days associated with body aches and nausea. She didn’t have any abdominal pain, bleeding manifestations or postural symptoms. On examination, she was flushed and febrile but was not pale or icteric. She was mildly dehydrated. Blood pressure was 100/70 mmHg, pulse rate 100 beats/min and capillary refilling time (CRFT) was less than 2 s. On abdominal examination, there was no free fluid. Lung fields were clear on respiratory system examination. Other systems examination was normal.

Her NS1 antigen was positive and serotype was identified as DEN1. She was managed as dengue fever with continuous monitoring. On the 3rd day of fever, she complained of retrosternal chest pain and undue tiredness. At that time her cardiovascular system examination was normal and electrocardiogram (ECG) showed acute T wave inversion in V2-V5 leads. Troponin I was negative and 2D echo showed global left ventricular hypokinesia and mild impairment of LV function. Ejection fraction was 40–45%. She was treated as having dengue fever complicated by myocarditis. Intravenous hydrocortisone 200 mg 8 hourly was administered for 2 days to reduce myocardial inflammation. On the 4rd day following admission, she complained of abdominal pain and ultrasound scanning revealed free fluid in hepato-renal pouch. Blood pressure was 100/70 mmHg, pulse rate 70 bpm, and CRFT was less than 2 s. She was taken to High Dependency Unit (HDU) and was managed as having DHF complicated with myocarditis with continuous monitoring and with careful administration of fluid to avoid fluid overload. She was discharged on day 7 of illness after recovering from critical phase of dengue fever. She was advised on limiting physical activities. During the follow up on day 14 of the illness, ECG showed reversal of T inversions. Echocardiogram showed improvement of left ventricular function with an ejection fraction of 55%.

Case 5: (acute GI bleeding and hepatitis in DF)

A-22-year old previously healthy male admitted to THP with a history of on and off fever for 10 days associated with 3 bouts of hematemesis and melaena. On examination, his pulse rate was 88 beats/m, blood pressure was 90/60 mmHg and CRFT was less than 2 s and lungs were normal. Abdomen was soft and there was no detectable free fluid. Rest of the examination was unremakable. Serology for dengue IgM and IgG were positive on admission. His liver enzymes were high on admission (AST 840 U/L and ALT 560 U/L) with a high INR value of 2.1. His complete blood count showed 11.5 g/dl of haemoglobin and platelet count of 144 × 10 9 /l. Ultrasound examination of abdomen did not show any evidence of leaking thus, DHF was excluded. Hence, the patient was managed as in primary dengue fever with bleeding manifestations. Intravenous fluids were given along with tranexamic acid and vitamin K to reduce bleeding. Intravenous infusion of omeprazole was continued for 24 h and converted to twice day intravenous boluses. He was started in intravenous N acetyl cysteine infusion as liver transaminases were high. His symptoms resolved within the next few days, with symptomatic management.

Case 6: (DEN 2 primary infection and bleeding into GIT and GUT)

A-12-year old previously well female child was transferred to THP from a private hospital due to fever for 5 days associated with melena, haematemesis and haematuria with passage of blood clots. She did not have abdominal pain or any other warning signs of dengue on admission.

On examination, she was ill looking, adequately hydrated and GCS was 15/15. Blood pressure was 125/75 mmHg, pulse rate was 90 beats per minute and capillary refilling time was less than 2 s. On respiratory examination lungs were clear and on abdominal examination the abdomen was soft and non tender. Rest of the clinical examination was normal. Both NS1 and IgM were positive and dengue PCR revealed serotype of DEN 2. Ultrasound examination of abdomen did not show any evidence of plasma leaking. She was managed as having primary dengue fever with bleeding manifestations. Her liver enzymes were only mildly elevated (AST 87 u/L and ALT 56 u/L) with a normal clotting profile. Complete blood count revealed hemoglobin of 7 g/dl and platelet count of 17 × 10 9 /μL. Due to low haemoglobin, she was transfused with 1 pint of blood and 4 units of platelets. Her symptoms resolved within the next few days.

Case 7: (DEN 2, severe diarrhoea, DHF, profound shock, sepsis and occult bleeding, need of massive transfusion)

A 14-year-old boy presented to THP with a history of fever for 2 days along with headache, arthralgia and myalgia. He did not complain of abdominal pain and did not have bleeding manifestations or any other warning symptoms. On examination, blood pressure was 110/70 mmHg and pulse rate was 100 beat per minute and capillary refilling time was less than 2 s. The abdomen was soft and non-tender and there was no free fluid. Lung fields were clear on respiratory system examination. Rest of the examination was normal. His NS-1 was positive and the PCR appeared as DEN 2 serotype. The patient was managed as having dengue fever. He continued to have fever spikes for 4 days following admission. On the 5th day following admission, he developed postural dizziness, vomiting and heavy diarrhoea. On examination, he was febrile, dehydrated, flushed and had warm peripheries. Blood pressure was 90/60 mmHg, pulse rate was 130 beats per minute and a capillary refilling time of 2 s. Ultrasound examination of abdomen revealed free fluid in the hepato-renal pouch with increased gall bladder wall thickness. He was clinically diagnosed as having DHF complicated with septic shock and gastroenteritis. He was taken to HDU and critical phase monitoring commenced. His c-reactive protein was high 112 mg/dl. Broad-spectrum intravenous antibiotics (ceftriaxone and metronidazole) were started cover the sepsis after taking blood and urine cultures. Within about 1 h, the patient deteriorated significantly and continued to have vomiting and diarrhoea. Blood pressure dropped to 60/30 mmHg and the pulse rate increased to 120 beats/min. Several fluid boluses were given including normal saline and IV Dextran 40. The haematocrit value dropped from 36 to 30 and patient went into decompensated shock with no urine output. He needed continuous transfusion of whole blood amounting to 9 pints over 20 h to maintain blood pressure and urine output. However, there were no obvious bleeding sites. Further, intravenous noradrenaline infusion supported the blood pressure. Gradually patient improved with fluid, blood, antibiotics and vasopressors. He was given intravenous antibiotics for total of 7 days. Vasopressor was gradually weaned off. He was plethoric during convalescence due to over transfusion and was discharged on day 8 of admission.

Case 8 (presenting as dysentery and in compensated shock in DHF)

A previously well 36-year-old Buddhist monk presented to THP with a history of a febrile illness with generalized malaise for 4 days duration. His main complaint was vomiting and diarrhea of same duration. He did not have any postural symptoms, bleeding manifestations or abdominal pain at presentation. On examination, he was febrile and was not pale or icteric. Blood pressure was 120/100 mmHg with a pulse rate of 110 beats per minute and capillary refilling time of 2 s. On respiratory system examination, there was bilateral plural effusion and on examination of the abdomen there was shifting dullness. Other systems examination was normal. Ultrasound examination of abdomen revealed moderate amount of free fluid in the abdomen. Blood and urine were taken for investigations. His NS 1 antigen was positive, and serotype was identified as DEN 2. The patient was immediately taken to HDU and was managed as compensated shock of dengue hemorrhagic fever. Initial investigations revealed a platelet count of 15 × 10 9 /l, and haematocrit of 57%. With meticulous fluid management he recovered. Thus, this patient had clinical picture of dysentery associated with DHF presenting at the peak of critical phase.

Case 9: (occult leaking of plasma leading to undetected decompensated shock)

A 51-one-year-old previously healthy female admitted with a history a febrile illness with arthralgia and myalgia for 4 days. Her NS1 antigen was positive on admission. She was ill and complained of postural dizziness and abdominal pain. On examination, she was ill looking, dehydrated and had bluish cold peripheries. She had central cyanosis and collapsed superficial veins. Her supine blood pressure was recorded as 90/80 mmHg and standing blood pressure was unable to measure due to severe postural symptoms. Capillary refilling time was prolonged, and her respiratory rate was 24 breaths per minute. Lungs were clear and clinically there was no evidence of free fluid in abdomen and pleura. She did not pass urine for 12 h. She was clinically diagnosed to have dengue haemorrhagic fever with decompensated shock. Then she was admitted to the HDU and critical phase management was started. Ultrasound scan of the abdomen did not show free fluid in peritoneal cavity despite patient was possibly in the peak of plasma leaking. However, 12 h after admission, repeat ultrasound scan showed thin rim of free fluid in the hepatorenal pouch. She was resuscitated with boluses of crystalloids and colloids., She became hemodynamically stable gradually and took about 8 h to gain warm peripheries. Fluid management and monitoring was continued, and her symptoms improved within the next 2 days. Although she went in to decompensated shock due to DHF, she had minimum detectable amount free fluid in the abdomen in the later phase of leaking.

Case 10: (DF complicating severe septic shock)

A 34-year-old female presented with a febrile illness with arthralgia and myalgia for 2 days duration. Her Dengue NS1 was positive. Her hemodynamic parameters were stable on admission. She was having continuous fever on day 6 of illness. There was no evidence of hemoconcentration or plasma leak and managed as uncomplicated dengue fever. She was kept on intravenous saline infusion at a slower rate. On 6th day of fever she developed cough and shortness of breath. Auscultation of lungs heard crepitations in bases. Over next 6 h she was not improving despite continuous infusion of normal saline and commencing antibiotics. Later, she became agitated and restless and was confused. She had warm peripheries despite blood pressure of 80/40 mmHg which further dropped to 60/30 mmHg. She had pulse rate of 108 beats/ min. There were widespread coarse crackles in the both lung fields involving all 3 zones. Her oxygen saturation dropped to 85% on room air. Her haematocrit remained within normal range. To counter the shock, she was given more intravenous normal saline, Dextran 40 and 2 units of blood transfusion. Then, she developed pulmonary oedema and required CPAP in the intensive care unit with high flow oxygen and intravenous frusemide. Patient was treated with intravenous meropenum 1 g 8 hourly and metronidazole. She had very high CRP and procalcitonin levels suggestive of severe sepsis. After 6 h of resuscitation her blood pressure got stabilized and she recovered completely over next 5 days. She was diagnosed as dengue fever complicated by septic shock probably originating from lungs even though, dengue shock syndrome (DSS) was contemplated at the outset.

Discussion and conclusion

Our case series compiles summaries of 10 confirmed dengue cases with wide array of unusual manifestation which are potentially fatal, in a single centre (THP) in the central hills of Sri Lanka. All these patients presented during mid-year outbreak of dengue in 2016 when serotype transition occurring from DEN 1 to DEN 2 that finally led to a massive outbreak of DEN 2 in 2017 in Sri Lanka. In these cases, females (n,6) out number males (n,4) and 7 patient had DHF. Out of 3 patients who had DF, 2 developed severe GI bleeding while other one developed severe septic shock that was mistaken for dengue shock syndrome (DSS) initially. Other unusual manifestations highlighted are hepatic dysfunction, myocarditis, erratic plama leak, ICH, occult blood loss, decompensated shock etc. Early detection of these manifestation and taking appropriate clinical decisions such as blood transfusions, antibiotics, and other empirical treatments saved all lives.

Most such manifestations of dengue infection are underreported, under recognized or not casually linked to dengue fever. Therefore, vigilance and anticipation are needed in managing dengue beyond the most common stable type of plasma leak in DHF.

Common life threatening complications related to DF and DHF include hepatic dysfunction leading to acute fulminant hepatic failure [ 3 ], musculoskeletal complications such as myositis and rhabdomyolysis [ 4 ], acute renal failure [ 5 ], cardiac complications such as myocarditis [ 6 ], life threatening bleeding such as gastrointestinal and intracranial bleeding [ 7 ], endocrine complications such as precipitating diabetic ketoacidosis [ 8 ] and neurological complications such as Guillain Barre syndrome and encephalopathy [ 9 ]. Early identification and early approach for appropriate management strategies are important to reduce morbidity and mortality of such cases. Better understanding of the disease dynamics has improved the outcome over time but still timely diagnosis and management is a challenge.

This case series comprises primary dengue infection, dengue fever (DF) and dengue hemorrhagic fever (DHF) all associated with unusual manifestaions. Importantly some life-threatening complications were observed in both primary dengue infection and DF without leaking. Patients in cases 1,2,3,4,7,8 and 9 developed DHF whereas patients in cases 5, 6 and 10 had DF. Some presented with bleeding manifestations while the others developed complications mentioned above.

Dengue can present with a diverse clinical spectrum ranging from asymptomatic infection or simple undifferentiated fever to DHF with multiorgan failure. Pathological hallmark of dengue hemorrhagic fever is increased capillary permeability with extravasation of fluids during the critical phase of dengue fever [ 3 , 10 ]. The onset of critical phase is determined by clinically or radiologically demonstrable pleura effusion or ascites and/or evidence of hemoconcentration as shown by increased haematocrit in serial measurements [ 3 , 11 ]. The critical phase lasts for a period of 24–48 h in which rate of plasma leak gradually peaks and comes down to the baseline. But this typical pattern is not appreciated all the time. Case 1 describes a young erratic leaker. His plasma leak peaked within 1st 12 h of critical phase evidenced by rapidly rising haematocrit and rapidly developing pleural effusions and ascites necessitating use of more than 60% of fluid quota within first 12 h. This type erratic leaker needs to be identified early with frequent monitoring of clinical parameters and haematocrit and fluid need to be titrated accordingly. The same patient had obvious fluid leak into peritoneal cavity and pleural spaces with hypoalbunaemia and took time for reabsorption. Case 9 describes a female who presented with decompensated shock. She had evidence of hemoconcentration with a high haematocrit. But on presentation clinically and ultrasonically she had no objective evidence of plasma leak into serous cavities. This highlights that although plasma leak is describes as selective to pleural, pericardial and peritoneal cavities, there can be substantial amount of fluid leaking in to 3rd space of unknown sites. Absence of objective fluid leak should not delay the treating physician making a diagnosis of DHF in the presence of evidence of intravascular volume depletion and hemoconcentration. However, frequent use of ultrasound examination has enhanced early detection of plasma leak. In THP, ultrasound scanners are available in the wards where dengue patients are treated to do bedside scaning without mobilizing patients to scanning rooms.

Liver dysfunction is a well-recognized feature in both dengue fever and DHF. Patients with dengue fever complaining of abdominal pain, nausea, vomiting and anorexia should alert the physician of the possibility of liver involvement [ 12 ]. Aetio-pathogenesis in liver dysfunction in dengue fever is yet to be elucidated. Direct effects of the virus or host immune response on liver cells, circulatory compromise, metabolic acidosis and/or hypoxia caused by hypotension or localized vascular leakage inside the liver are possible mechanisms postulated to explain the liver dysfunction [ 13 , 14 ]. Case 2 describes patient with DHF developing acute liver failure and case 5 describes a patient with DF without leaking developing liver dysfunction, coagulopathy and gastrointestinal bleeding. Both cases were successfully managed with adequately maintaining the hydration status and intravenous N acetyl cysteine. NAC scavenges free radicals, improves antioxidant defense and acts as a vasodilator to improve oxygen delivery and consumption [ 15 ]. However, efficacy of NAC needs to be validated with further studies.

Bleeding manifestations are seen both in dengue fever and dengue hemorrhagic fever. Despite the name, cardinal feature that differentiate dengue fever from DHF is not hemorrhage but leaking. The underlying mechanisms responsible for bleeding in dengue infections remain poorly understood. Thrombocytopenia is universal in DHF and most of the patients with DF [ 16 ]. Platelet functions is abnormal in acute dengue fever mainly due to impaired ADP mediated platelet aggregation [ 17 ].Isarangkura et al. reported that platelet survival is less in acute dengue fever [ 18 ]. Mild prolongation of prothrombin time and activated partial thromboplastin times with reduction in fibrinogen levels were reported in some studies in patients without liver involvement [ 19 , 20 ]. Patients with prolonged shock with multi-organ dysfunction and those with acute liver failure had major gastrointestinal bleeds contributed by deranged clotting and gut ischemia. Case 5 describes a patient with DF without leaking who had normal platelets with severe liver involvement leading to coagulopathy and gastrointestinal bleeding. In contrast in case 6, a primary DF patient developed severe gastrointestinal bleeding needing blood and platelet transfusions. Her liver enzymes were marginally elevated and had a normal clotting profile. Her main risk factor for a gastrointestinal bleed, haematuria was low platelet count.

Intracranial hemorrhage in dengue fever is a rare but a grave complication. Mechanism of intracranial bleeding is still not clearly described, it is postulated that it could be due to the interplay between coagulopathy, platelet dysfunction, thrombocytopenia, and vasculopathy [ 21 , 22 ]. In our patient described in case 3 presented in the peak of leaking with postural symptoms. On admission, his platelet count was16 × 10 9 /μl. He had history of a fall with head impact and soon after admission patient sustained a generalized tonic clonic fit. Later he was found to have bilateral frontal lobe hemorrhages. This could be either traumatic following the fall or could be spontaneous which might have caused the fall. Management of an ICH in a dengue patient is controversial as the causative factors such as vasculopathy and platelet dysfunction are usually still present and irreversible while surgery is undertaken. No studies have been performed on place for surgery for ICH in dengue fever. Low platelets are the main risk factor for an ICH in dengue fever. There is no consensus on when to transfuse platelets and place for primary prophylaxis. Some studies have recommended prophylaxis platelet transfusions when the platelet count is very low [ 23 , 24 ]. In 2011, Kurukularatne et al. strongly concluded that prophylactic platelet transfusion is associated with hazards and wastage without any hematological benefit and therefore, should not be adopted as a routine clinical practice [ 25 ]. Our patient received platelet transfusion as a secondary prophylactic measure as the platelet count was very low.

Dengue fever and DHF are associated with a wide spectrum cardiac complication. Kularatne et al. showed that 62.5% of 120 adults with dengue fever had an abnormal electrocardiogram [ 26 ]. Most cardiac complications are clinically mild and self-limiting, therefore, they are under diagnosed [ 27 ]. Myocardial involvement in dengue is yet to be fully described, but it can be due to direct viral invasion of the myocardium or cytokine mediated immune injury [ 28 ]. In case 4, young patient had evidence of myocarditis in ECG and left ventricular global hypokinesia in the 2D Echo. She was managed conservatively with meticulous fluid management and with a short course of steroids. Theoretically, steroids help to reduce inflammation of myocardium, thus improving contractility. Her follow up Echo in 2 weeks showed normalization of left ventricular systolic function.

Clinically considerable proportion of dengue patients who presented to the hospital can have bacterial co-infection [ 29 ]. Bacterial co-infection can be easily overlooked in the dengue epidemic setting. Delay in diagnosis and delay in anti-microbial therapy will have adverse outcome. Bacteremia in dengue fever is mainly Gram negative. It is probably caused by the breakdown of the intestinal mucosal barrier in severe dengue infection. In Case 7, the patient had DHF complicated with septic shock. The focus of sepsis is probably the gut, as he had diarrhoea and sepsis developed during leaking phase and gut ischemia probable led to breach in mucosal defense and gram-negative sepsis. Low blood pressure in tachycardia could have been easily overlooked attributing to dengue shock syndrome, but the disproportionately high pulse rate and warm peripheries in the background of shock alerted the treating physician of the possible underlying sepsis. Prompt use of antibiotics and judicious use of vasopressors were lifesaving. It is intriguing that he needed massive transfusions to maintain his blood pressure and save the life. This case provide empirical evidence for blood transfusion sever dengue infection Moreover, Case 10 describes a patient developed dengue fever and septic shock probably originating from the lung. Patient was treated with blood transfusion and intravenous crystalloids and colloids to overcome the shock which resulted in pulmonary edema. Judicious use of vasopressors is important in such instance to prevent volume overload. Supportive respiratory care over many hours maintained the oxygenation. The Case 8 describe presentation of dengue predominantly with diarrhea that might mislead the clinician as bacillary dysentery.

Lessons learnt from managing difficult cases of dengue as we presented here need sharing. Similar cases or situations may be happening at any given time in the globe as dengue is mostly seen everywhere. These clinical observations needs explanation on pathophysiological basis, but the knowledge about pathology and pathophysiology in dengue needs further improvement. Better treatment options are needed to improve the outcome of dengue.

Abbreviations

Adenine di-Phosphate

Alanine transaminase

Aspartate transaminase

Continuous Positive Airway Pressure

Capillary Refilling Time

Dengue virus serotype 1

Dengue Haemorrhagic Fever

Full Blood Count

High Dependency Unit

Intra Cranial Haemorrhage

N-Acetyl Cysteine

Polymerase chain reaction

Packed Cell Volume

Teaching Hospital Peradeniya

Halstead SB. Dengue. CurrOpin Infect Dis. 2002;15(5):471–6.

Article   Google Scholar  

Wilder-Smith A, Schwartz E. Dengue in travelers. N Engl J Med. 2005;353:924–32.

Article   CAS   Google Scholar  

Kularatne SAM. Dengue fever. BMJ. 2015;351:h4661. https://doi.org/10.1136/BMJ.h4661 .

Article   PubMed   Google Scholar  

Dalugama C, Ralapanawa U, Jayalath T. Dengue myositis and review of literature. Clin Case Rep Res Trials. 2017;2:16–8.

Google Scholar  

Lizarraga KJ, Nayer A. Dengue-associated kidney disease. J Nephropathol. 2014;3(2):57–62 http://doi.org/10.12860/jnp.2014.13.

PubMed   Google Scholar  

Wali JP, Biswas A, Chandra S, Malhotra A, Aggarwal P, Handa R, Wig N, Bahl VK. Cardiac involvement in dengue haemorrhagic fever. Int J Cardiol. 1998;64(1):31–6.

Kumar R, Prakash O, Sharma BS. Intracranial hemorrhage in dengue fever: management and outcome: a series of 5 cases and review of literature. Surg Neurol. 2009;72(4):429–33.

Dalugama C, Gawarammana IB. Dengue hemorrhagic fever complicated with transient diabetic ketoacidosis: a case report. J Med Case Rep. 2017;11(1):302.

Ralapanawa DM, Kularatne SA, Jayalath WA. Guillain-Barre syndrome following dengue fever and literature review. BMC Res Notes. 2015;8:729. https://doi.org/10.1186/s13104-015-1672-0 .

Article   PubMed   PubMed Central   Google Scholar  

Stephenson JR. Understanding dengue pathogenesis: implications for vaccine design. Bull World Health Organ. 2005;83:308–14.

PubMed   PubMed Central   Google Scholar  

Guidelines on Management of Dengue Fever and Hemorrhagic Fever in adults: Epidemiology Unit, Ministry of Health; 2012. http://www.epid.gov.lk/web/images/pdf/Publication/guidelines_for_the_management_of_df_and_dhf_in_adults.pdf

Karoli R, Fatima J, Siddiqi Z, Kazmi KI, Sultania AR. Clinical profile of dengue infection at a teaching Hospital in North India. J Infect Dev Ctries. 2012;6:551–4.

Itha S, Kashyap R, Krishnani N, Saraswat VA, Choudhuri G, Aggarwal R. Profile of liver involvement in dengue virus infection. Natl Med J India. 2005;18:127–30.

Kularatne SAM, Imbulpitiya IVB, Abeysekera RA, Waduge R, Rajapakse RPVJ, Weerakoon KGAD. Extensive haemorrhagic necrosis of liver is an unpredictable fatal complication in dengue infection: a postmortem study. BMC Infect Dis. 2014;14:141.

Sklar GE, Subramaniam M. Acetylcysteine treatment for non-acetaminopheninduced acute liver failure. Ann Pharmacother. 2004;498–500(23):38.

World Health Organization. Dengue haemorrhagic fever: diagnosis, treatment, prevention and control. 2nd edi ed. Geneva: WHO; 1997. http://www.who.int/csr/resources/publications/dengue/Denguepublication/en/

Srichaikul TA, Nimmannitya SU, Sripaisarn T, Kamolsilpa MA, Pulgate CH. Platelet function during the acute phase of dengue hemorrhagic fever. Southeast Asian J Trop Med Public Health. 1989;20(1):19–25.

CAS   PubMed   Google Scholar  

Isarangkura P, Tuchinda S. The behavior of transfused platelets in dengue hemorrhagic fever. Southeast Asian J Trop Med Public Health. 1993;24:222–4.

Mitrakul C, Poshyachinda M, Futrakul P, Sangkawibha N, Ahandrik S. Hemostatic and platelet kinetic studies in dengue hemorrhagic fever. Am J Trop Med Hyg. 1977;26(5):975–84.

Funahara Y, Shirahata A, Setiabudy-dharma RA. DHF characterized by acute type DIC with increased vascular permeability. Southeast Asian J Trop Med Public Health. 1987;18(3):346–50.

Cam BV, Fonsmark L, Hue NB, Phuong NT, Poulsen A, Heegaard ED. Prospective case-control study of encephalopathy in children with dengue hemorrhagic fever. Am J Trop Med Hyg. 2001;65:848–51.

Puccioni-Sohler M, Soares CN, Papaiz-Alvarenga R, Castro MJ, Faria LC, Peralta JM. Neurologic dengue manifestations associated with intrathecal specific immune response. Neurology. 2009;73:1413–7.

Makroo RN, Raina V, Kumar P, Kanth RK. Role of platelet transfusion in the management of dengue patients in a tertiary care hospital. Asian J Transfus Sci. 2007;1:4–7.

Dutta AK, Biswas A, Baruah K, Dhariwal AC. National guidelines for diagnosis and management of dengue fever/dengue haemorrhagic fever and dengue shock syndrome. J Indian Med Assoc. 2011;109:30–5.

Kurukularatne C, Dimatatac F, Teo DL, Lye DC, Leo YS. When less is more: can we abandon prophylactic platelet transfusion in dengue fever? Ann Acad Med Singap. 2011;40:539–45.

Kularatne SAM, Pathirage MMK, Kumarasiri PVR, Gunasena S, Mahindawanse SI. Cardiac complications of a dengue fever outbreak in Sri Lanka, 2005. Trans R Soc Trop Med Hyg. 2007;101(8):804–8.

Satarasinghe RL, Arultnithy K, Amerasena NL, Bulugahapitiya U, Sahayam DV. Asymptomatic myocardial involvement in acute dengue virus infection in a cohort of adult Sri Lankans admitted to a tertiary referral Centre. Br J Cardiol. 2007;14:171–3.

Hober D, Poli L, Roblin B, Gestas P, Chungue E, Granic G, Imbert P, Pecarere JL, Vergez-Pascal R, Watter P, Maniez-Montreuil M. Serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1 beta (IL-1 beta) in dengue-infected patients. Am J Trop Med Hyg. 1993;48(3):324–31.

See KC, Phua J, Yip HS, Yeo LL, Lim TK. Identification of concurrent bacterial infection in adult patients with Dengue. Am J Trop Med Hyg. 2013;89(4):804–10 http://doi.org/10.4269/ajtmh.13-0197.

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S. A. M. Kularatne, Udaya Ralapanawa, Chamara Dalugama, Jayanika Jayasinghe & Sawandika Rupasinghe

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SAMK, UR, PK and CD managed the patients. JJ and SR collected the data. All authors did intellectual contribution and participated in drafting the manuscript. All authors read and approved the final manuscript.

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Correspondence to Udaya Ralapanawa .

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Kularatne, S.A.M., Ralapanawa, U., Dalugama, C. et al. Series of 10 dengue fever cases with unusual presentations and complications in Sri Lanka: a single centre experience in 2016. BMC Infect Dis 18 , 674 (2018). https://doi.org/10.1186/s12879-018-3596-5

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Received : 14 June 2018

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Published : 18 December 2018

DOI : https://doi.org/10.1186/s12879-018-3596-5

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• Expanded dengue syndrome
• Fulminant liver failure
• Myocarditis
• Septic shock
• Dengue shock syndrome

BMC Infectious Diseases

ISSN: 1471-2334

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Dengue Clinical Presentation

• Author: Darvin Scott Smith, MD, MSc, DTM&H, FIDSA; Chief Editor: Michael Stuart Bronze, MD  more...
• Sections Dengue
• Practice Essentials
• Pathophysiology
• Epidemiology
• Patient Education
• Physical Examination
• Approach Considerations
• Complete Blood Cell Count
• Metabolic Panel and Liver Enzymes
• Coagulation Studies
• Serum Studies
• Ultrasonography
• Case Definitions
• Suspected Dengue
• Severe Dengue
• Diet and Activity
• Vaccine Development
• Consultations
• Medication Summary
• Volume Expanders
• Vaccines, Live, Viral
• Questions & Answers
• Media Gallery

Patients with dengue will have a history of living in, or recent travel to, a region where the disease is endemic. The incubation period is 3-14 days (average, 4-7 days); symptoms that begin more than 2 weeks after a person departs from an endemic area probably are not due to dengue.

Many patients experience a prodrome of chills, erythematous mottling of the skin, and facial flushing (a sensitive and specific indicator of dengue fever). The prodrome may last for 2-3 days. Children younger than 15 years usually have a nonspecific febrile syndrome, which may be accompanied by a maculopapular rash. Classic dengue fever begins with sudden onset of fever, chills, and severe (termed breakbone) aching of the head, back, and extremities, as well as other symptoms. The fever lasts 2-7 days and may reach 41°C. Fever that lasts longer than 10 days probably is not due to dengue.

Pain and other accompanying symptoms may include any of the following:

• Retro-orbital pain
• General body pain (arthralgias, myalgias)
• Nausea and vomiting (however, diarrhea is rare)
• Altered taste sensation
• Sore throat
• Mild hemorrhagic manifestations (eg, petechiae, bleeding gums, epistaxis, menorrhagia, hematuria)
• Lymphadenopathy

Rash in dengue fever is a maculopapular or macular confluent rash over the face, thorax, and flexor surfaces, with islands of skin sparing. The rash typically begins on Day 3 and persists 2-3 days.

Fever typically abates with the cessation of viremia. Occasionally, and more commonly in children, the fever abates for a day and then returns, a pattern that has been called saddleback fever. A second rash may occur within 1-2 days of defervescence, lasting 1-5 days; it is morbilliform, is maculopapular, spares the palms and soles, and occasionally desquamates.

Recovery is complete but slow, with fatigue and exhaustion often persisting after the fever has subsided. The convalescent phase may last for 2 weeks.

Patients are at risk for development of dengue hemorrhagic fever or dengue shock syndrome at approximately the time of defervescence. Abdominal pain in conjunction with restlessness, change in mental status, hypothermia, and a drop in the platelet count presages the development of dengue hemorrhagic fever.

Of patients with dengue hemorrhagic fever, 90% are younger than 15 years. The initial phase of dengue hemorrhagic fever is similar to that of dengue fever and other febrile viral illnesses. Shortly after the fever breaks (or sometimes within 24 hours before), signs of plasma leakage appear, along with the development of hemorrhagic symptoms such as bleeding from sites of trauma, gastrointestinal bleeding, and hematuria. Patients may also present with abdominal pain, vomiting, febrile seizures (in children), and a decreased level of consciousness.

If left untreated, dengue hemorrhagic fever most likely progresses to dengue shock syndrome. Common symptoms in impending shock include abdominal pain, vomiting, and restlessness. Patients also may have symptoms related to circulatory failure.

Dengue fever presents in a nonspecific manner and may not be distinguishable from other viral or bacterial illness. According to the Pan American Health Organization (PAHO), the clinical description of dengue fever is an acute febrile illness of 2-7 days duration associated with 2 or more of the following:

• Severe and generalized headache
• Severe myalgias, especially of the lower back, arms, and legs
• Arthralgias, usually of the knees and shoulders
• Characteristic rash
• Hemorrhagic manifestations

Additional findings may include the following:

• Injected conjunctivae
• Facial flushing, a sensitive and specific predictor of dengue infection
• Inflamed pharynx
• Nausea and vomiting
• Nonproductive cough
• Tachycardia, bradycardia, and conduction defects

Up to half of patients with dengue fever develop a characteristic rash. The rash is variable and may be maculopapular or macular. Petechiae and purpura may develop as hemorrhagic manifestations. Hemorrhagic manifestations most commonly include petechiae and bleeding at venipuncture sites.

A tourniquet test often is positive. This test is performed by inflating a blood pressure cuff on the upper arm to midway between diastolic and systolic blood pressures for 5 minutes. The results are considered to be positive if more than 20 petechiae per square inch are observed on the skin in the area that was under pressure. Other hemorrhagic manifestations include nasal or gingival bleeding, melena, hematemesis, and menorrhagia.

Neurologic manifestations such as seizures and encephalitis/encephalopathy have been reported in rare cases of dengue infection. Some of these cases did not display other typical features of dengue infection. Other neurologic complications associated with dengue infection include neuropathies, Guillain-Barré syndrome, and transverse myelitis.

Dengue hemorrhagic fever

Findings for dengue hemorrhagic fever are similar to those for dengue fever and include the following:

Biphasic fever curve

Hemorrhagic findings more pronounced than in dengue fever

Signs of peritoneal effusion, pleural effusion, or both

Minimal criteria for the diagnosis of dengue hemorrhagic fever, according to the World Health Organization (WHO), are as follows [ 65 ] :

Hemorrhagic manifestations (eg, hemoconcentration, thrombocytopenia, positive tourniquet test)

Circulatory failure, such as signs of vascular permeability (eg, hypoproteinemia, effusions)

Hepatomegaly

In addition, conjunctival injection develops in approximately one third of patients with dengue hemorrhagic fever. Optic neuropathy has been reported and occasionally results in permanent and significant visual impairment. [ 66 ] Pharyngeal injection develops in almost 97% of patients with dengue hemorrhagic fever. Generalized lymphadenopathy is observed.

Hepatomegaly is present more often in dengue shock syndrome than in milder cases. Hepatic transaminase levels may be mildly to moderately elevated. Encephalopathy is a rare complication that may result from a combination of cerebral edema, intracranial hemorrhage, anoxia, hyponatremia, and hepatic injury.

Dengue shock syndrome

Findings of dengue shock syndrome include the following:

Hypotension

Bradycardia (paradoxical) or tachycardia associated with hypovolemic shock

Hypothermia

Narrow pulse pressure (< 20 mm Hg)

Signs of decreased peripheral perfusion

Santos LLM, de Aquino EC, Fernandes SM, Ternes YMF, Feres VCR. Dengue, chikungunya, and Zika virus infections in Latin America and the Caribbean: a systematic review. Rev Panam Salud Publica . 2023. 47:e34. [QxMD MEDLINE Link] .

Schaefer TJ, Panda PK, Wolford RW. Dengue Fever. StatPearls . 2023 Jan. [QxMD MEDLINE Link] . [Full Text] .

Tayal A, Kabra SK, Lodha R. Management of Dengue: An Updated Review. Indian J Pediatr . 2023 Feb. 90 (2):168-177. [QxMD MEDLINE Link] .

Kok BH, Lim HT, Lim CP, Lai NS, Leow CY, Leow CH. Dengue virus infection - a review of pathogenesis, vaccines, diagnosis and therapy. Virus Res . 2023 Jan 15. 324:199018. [QxMD MEDLINE Link] .

World Health Organization. Dengue and severe dengue fact sheet. WHO. Available at https://www.who.int/mediacentre/factsheets/fs117/en/ . April 2017; Accessed: April 11, 2023.

Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL, et al. The global distribution and burden of dengue. Nature . 2013 Apr 25. 496 (7446):504-7. [QxMD MEDLINE Link] .

Brady OJ, Gething PW, Bhatt S, Messina JP, Brownstein JS, Hoen AG, et al. Refining the global spatial limits of dengue virus transmission by evidence-based consensus. PLoS Negl Trop Dis . 2012. 6 (8):e1760. [QxMD MEDLINE Link] .

Wilson ME, Chen LH. Dengue: update on epidemiology. Curr Infect Dis Rep . 2015 Jan. 17 (1):457. [QxMD MEDLINE Link] .

WHO. Ten threats to global health in 2019. World Health Organization. Available at https://www.who.int/news-room/spotlight/ten-threats-to-global-health-in-2019 . 2019; Accessed: April 11, 2023.

Kyle JL, Harris E. Global spread and persistence of dengue. Annu Rev Microbiol . 2008. 62:71-92. [QxMD MEDLINE Link] .

Statler J, Mammen M, Lyons A, Sun W. Sonographic findings of healthy volunteers infected with dengue virus. J Clin Ultrasound . 2008 Sep. 36(7):413-7. [QxMD MEDLINE Link] .

Gubler DJ. Cities spawn epidemic dengue viruses. Nat Med . 2004 Feb. 10(2):129-30. [QxMD MEDLINE Link] .

Wilder-Smith A, Gubler DJ. Geographic expansion of dengue: the impact of international travel. Med Clin North Am . 2008 Nov. 92(6):1377-90, x. [QxMD MEDLINE Link] .

Messina JP, Brady OJ, Scott TW, Zou C, Pigott DM, Duda KA, et al. Global spread of dengue virus types: mapping the 70 year history. Trends Microbiol . 2014 Mar. 22 (3):138-46. [QxMD MEDLINE Link] . [Full Text] .

Halstead SB. Dengue. Lancet . 2007 Nov 10. 370(9599):1644-52. [QxMD MEDLINE Link] .

Chowell G, Torre CA, Munayco-Escate C, Suárez-Ognio L, López-Cruz R, Hyman JM. Spatial and temporal dynamics of dengue fever in Peru: 1994-2006. Epidemiol Infect . 2008 Dec. 136(12):1667-77. [QxMD MEDLINE Link] .

Osterweil N. Dengue 'Under-recognized' as Source of Febrile Illness in US. Medscape Medical News. Jan 23 2014. Available at https://www.medscape.com/viewarticle/819656 . Accessed: April 11, 2023.

Sharp TM, Gaul L, Muehlenbachs A, Hunsperger E, Bhatnagar J, Lueptow R, et al. Fatal hemophagocytic lymphohistiocytosis associated with locally acquired dengue virus infection - new Mexico and Texas, 2012. MMWR Morb Mortal Wkly Rep . 2014 Jan 24. 63(3):49-54. [QxMD MEDLINE Link] .

Freedman DO, Weld LH, Kozarsky PE, Fisk T, Robins R, von Sonnenburg F. Spectrum of disease and relation to place of exposure among ill returned travelers. N Engl J Med . 2006 Jan 12. 354(2):119-30. [QxMD MEDLINE Link] .

Liu-Helmersson J, Quam M, Wilder-Smith A, Stenlund H, Ebi K, Massad E, et al. Climate Change and Aedes Vectors: 21st Century Projections for Dengue Transmission in Europe. EBioMedicine . 2016 May. 7:267-77. [QxMD MEDLINE Link] .

CDC. Imported dengue--United States, 1997 and 1998. MMWR Morb Mortal Wkly Rep . 2000 Mar 31. 49(12):248-53. [QxMD MEDLINE Link] . [Full Text] .

Engelthaler DM, Fink TM, Levy CE, Leslie MJ. The reemergence of Aedes aegypti in Arizona. Emerg Infect Dis . 1997 Apr-Jun. 3(2):241-2. [QxMD MEDLINE Link] . [Full Text] .

Chye JK, Lim CT, Ng KB, et al. Vertical transmission of dengue. Clin Infect Dis . 1997 Dec. 25(6):1374-7. [QxMD MEDLINE Link] .

Wagner D, de With K, Huzly D, Hufert F, Weidmann M, Breisinger S, et al. Nosocomial acquisition of dengue. Emerg Infect Dis . 2004 Oct. 10(10):1872-3. [QxMD MEDLINE Link] .

Arragain L, Dupont-Rouzeyrol M, O'Connor O, Sigur N, Grangeon JP, Huguon E, et al. Vertical Transmission of Dengue Virus in the Peripartum Period and Viral Kinetics in Newborns and Breast Milk: New Data. J Pediatric Infect Dis Soc . 2017 Nov 24. 6 (4):324-331. [QxMD MEDLINE Link] .

Lalle E, Colavita F, Iannetta M, Gebremeskel Teklè S, Carletti F, Scorzolini L, et al. Prolonged detection of dengue virus RNA in the semen of a man returning from Thailand to Italy, January 2018. Euro Surveill . 2018 May. 23 (18): [QxMD MEDLINE Link] .

Liew CH. The first case of sexual transmission of dengue in Spain. J Travel Med . 2020 Feb 3. 27 (1): [QxMD MEDLINE Link] .

Dejnirattisai W, Duangchinda T, Lin CL, Vasanawathana S, Jones M, Jacobs M, et al. A complex interplay among virus, dendritic cells, T cells, and cytokines in dengue virus infections. J Immunol . 2008 Nov 1. 181(9):5865-74. [QxMD MEDLINE Link] .

Halstead SB, Heinz FX, Barrett AD, Roehrig JT. Dengue virus: molecular basis of cell entry and pathogenesis, 25-27 June 2003, Vienna, Austria. Vaccine . 2005 Jan 4. 23(7):849-56. [QxMD MEDLINE Link] .

Limjindaporn T, Wongwiwat W, Noisakran S, Srisawat C, Netsawang J, Puttikhunt C, et al. Interaction of dengue virus envelope protein with endoplasmic reticulum-resident chaperones facilitates dengue virus production. Biochem Biophys Res Commun . 2009 Feb 6. 379(2):196-200. [QxMD MEDLINE Link] .

Zhang JL, Wang JL, Gao N, Chen ZT, Tian YP, An J. Up-regulated expression of beta3 integrin induced by dengue virus serotype 2 infection associated with virus entry into human dermal microvascular endothelial cells. Biochem Biophys Res Commun . 2007 May 11. 356(3):763-8. [QxMD MEDLINE Link] .

Rothman AL, Ennis FA. Immunopathogenesis of Dengue hemorrhagic fever. Virology . 1999 Apr 25. 257(1):1-6. [QxMD MEDLINE Link] .

Chen LC, Lei HY, Liu CC, Shiesh SC, Chen SH, Liu HS. Correlation of serum levels of macrophage migration inhibitory factor with disease severity and clinical outcome in dengue patients. Am J Trop Med Hyg . 2006 Jan. 74(1):142-7. [QxMD MEDLINE Link] .

Green S, Rothman A. Immunopathological mechanisms in dengue and dengue hemorrhagic fever. Curr Opin Infect Dis . 2006 Oct. 19(5):429-36. [QxMD MEDLINE Link] .

Guzman MG, Alvarez M, Rodriguez-Roche R, Bernardo L, Montes T, Vazquez S. Neutralizing antibodies after infection with dengue 1 virus. Emerg Infect Dis . 2007 Feb. 13(2):282-6. [QxMD MEDLINE Link] .

Restrepo BN, Ramirez RE, Arboleda M, Alvarez G, Ospina M, Diaz FJ. Serum levels of cytokines in two ethnic groups with dengue virus infection. Am J Trop Med Hyg . 2008 Nov. 79(5):673-7. [QxMD MEDLINE Link] .

Rothman AL. Dengue: defining protective versus pathologic immunity. J Clin Invest . 2004 Apr. 113(7):946-51. [QxMD MEDLINE Link] .

de Macedo FC, Nicol AF, Cooper LD, Yearsley M, Pires AR, Nuovo GJ. Histologic, viral, and molecular correlates of dengue fever infection of the liver using highly sensitive immunohistochemistry. Diagn Mol Pathol . 2006 Dec. 15(4):223-8. [QxMD MEDLINE Link] .

Shah I. Dengue and liver disease. Scand J Infect Dis . 2008. 40(11-12):993-4. [QxMD MEDLINE Link] .

Dejnirattisai W, Jumnainsong A, Onsirisakul N, et al. Cross-reacting antibodies enhance dengue virus infection in humans. Science . 2010 May 7. 328(5979):745-8. [QxMD MEDLINE Link] .

Schmidt AC. Response to dengue fever--the good, the bad, and the ugly?. N Engl J Med . 2010 Jul 29. 363(5):484-7. [QxMD MEDLINE Link] .

Kurane I, Innis BL, Nimmannitya S, Nisalak A, Meager A, Ennis FA. High levels of interferon alpha in the sera of children with dengue virus infection. Am J Trop Med Hyg . 1993 Feb. 48(2):222-9. [QxMD MEDLINE Link] .

Ojha A, Nandi D, Batra H, Singhal R, Annarapu GK, Bhattacharyya S, et al. Platelet activation determines the severity of thrombocytopenia in dengue infection. Sci Rep . 2017 Jan 31. 7:41697. [QxMD MEDLINE Link] .

Hottz ED, Oliveira MF, Nunes PC, Nogueira RM, Valls-de-Souza R, Da Poian AT, et al. Dengue induces platelet activation, mitochondrial dysfunction and cell death through mechanisms that involve DC-SIGN and caspases. J Thromb Haemost . 2013 May. 11 (5):951-62. [QxMD MEDLINE Link] .

Wang E, Ni H, Xu R, Barrett AD, Watowich SJ, Gubler DJ. Evolutionary relationships of endemic/epidemic and sylvatic dengue viruses. J Virol . 2000 Apr. 74(7):3227-34. [QxMD MEDLINE Link] .

Centers for Disease Control and Prevention Web site. CDC traveler's health page. Dengue. CDC. Available at https://www.cdc.gov/Dengue/travelOutbreaks/ . Accessed: April 11, 2023.

Chen WS, Wong CH, Cillekens L. Dengue antibodies in a suburban community in Malaysia. Med J Malaysia . 2003 Mar. 58(1):142-3. [QxMD MEDLINE Link] .

Istúriz RE, Gubler DJ, Brea del Castillo J. Dengue and dengue hemorrhagic fever in Latin America and the Caribbean. Infect Dis Clin North Am . 2000 Mar. 14(1):121-40, ix. [QxMD MEDLINE Link] .

Hotez PJ, Bottazzi ME, Franco-Paredes C, Ault SK, Periago MR. The neglected tropical diseases of Latin America and the Caribbean: a review of disease burden and distribution and a roadmap for control and elimination. PLoS Negl Trop Dis . 2008 Sep 24. 2(9):e300. [QxMD MEDLINE Link] . [Full Text] .

Centers for Disease Control and Prevention (CDC). Travel-associated Dengue surveillance - United States, 2006-2008. MMWR Morb Mortal Wkly Rep . 2010 Jun 18. 59(23):715-9. [QxMD MEDLINE Link] . [Full Text] .

Centers for Disease Control and Prevention (CDC). Locally acquired Dengue--Key West, Florida, 2009-2010. MMWR Morb Mortal Wkly Rep . 2010 May 21. 59(19):577-81. [QxMD MEDLINE Link] .

Rey JR. Dengue in Florida (USA). Insects . 2014 Dec 16. 5 (4):991-1000. [QxMD MEDLINE Link] .

Malavige GN, Fernando S, Fernando DJ, Seneviratne SL. Dengue viral infections. Postgrad Med J . 2004 Oct. 80(948):588-601. [QxMD MEDLINE Link] . [Full Text] .

Stephenson JR. Understanding dengue pathogenesis: implications for vaccine design. Bull World Health Organ . 2005 Apr. 83(4):308-14. [QxMD MEDLINE Link] . [Full Text] .

World Health Organization. Dengue and Severe Dengue. WHO. Available at https://www.who.int/news-room/fact-sheets/detail/dengue-and-severe-dengue . March 17, 2023; Accessed: April 11. 2023.

Lin CC, Huang YH, Shu PY, et al. Characteristic of dengue disease in Taiwan: 2002-2007. Am J Trop Med Hyg . 2010 Apr. 82(4):731-9. [QxMD MEDLINE Link] . [Full Text] .

Anderson KB, Chunsuttiwat S, Nisalak A, Mammen MP, Libraty DH, Rothman AL. Burden of symptomatic dengue infection in children at primary school in Thailand: a prospective study. Lancet . 2007 Apr 28. 369(9571):1452-9. [QxMD MEDLINE Link] .

Anker M, Arima Y. Male-female differences in the number of reported incident dengue fever cases in six Asian countries. Western Pac Surveill Response J . 2011 Apr. 2 (2):17-23. [QxMD MEDLINE Link] .

Lahiri M, Fisher D, Tambyah PA. Dengue mortality: reassessing the risks in transition countries. Trans R Soc Trop Med Hyg . 2008 Oct. 102(10):1011-6. [QxMD MEDLINE Link] .

Beatty ME, Beutels P, Meltzer MI, et al. Health economics of dengue: a systematic literature review and expert panel's assessment. Am J Trop Med Hyg . 2011 Mar. 84(3):473-88. [QxMD MEDLINE Link] . [Full Text] .

Shepard DS, Coudeville L, Halasa YA, Zambrano B, Dayan GH. Economic impact of dengue illness in the Americas. Am J Trop Med Hyg . 2011 Feb. 84(2):200-7. [QxMD MEDLINE Link] . [Full Text] .

Suaya JA, Shepard DS, Siqueira JB, et al. Cost of dengue cases in eight countries in the Americas and Asia: a prospective study. Am J Trop Med Hyg . 2009 May. 80(5):846-55. [QxMD MEDLINE Link] .

WHO. Dengue and Severe Dengue. World Health Organization. Available at https://www.who.int/health-topics/dengue-and-severe-dengue . Accessed: April 11, 2023.

Sanjay S, Wagle AM, Au Eong KG. Dengue optic neuropathy. Ophthalmology . 2009 Jan. 116(1):170; author reply 170. [QxMD MEDLINE Link] .

Teves Maria A. Wrong treatment most common cause of dengue fatality. ABS/CBN News. Available at https://www.abs-cbnnews.com/nation/09/03/09/wrong-treatment-most-common-cause-dengue-fatality . Accessed: April 11, 2023.

Bottieau E, Clerinx J, Van den Enden E, Van Esbroeck M, Colebunders R, Van Gompel A. Fever after a stay in the tropics: diagnostic predictors of the leading tropical conditions. Medicine (Baltimore) . 2007 Jan. 86(1):18-25. [QxMD MEDLINE Link] .

Malhotra N, Chanana C, Kumar S. Dengue infection in pregnancy. Int J Gynaecol Obstet . 2006 Aug. 94(2):131-2. [QxMD MEDLINE Link] .

Singh N, Sharma KA, Dadhwal V, Mittal S, Selvi AS. A successful management of dengue fever in pregnancy: report of two cases. Indian J Med Microbiol . 2008 Oct-Dec. 26(4):377-80. [QxMD MEDLINE Link] .

Warrilow D, Northill JA, Pyke A, Smith GA. Single rapid TaqMan fluorogenic probe based PCR assay that detects all four dengue serotypes. J Med Virol . 2002 Apr. 66(4):524-8. [QxMD MEDLINE Link] .

Kong YY, Thay CH, Tin TC, Devi S. Rapid detection, serotyping and quantitation of dengue viruses by TaqMan real-time one-step RT-PCR. J Virol Methods . 2006 Dec. 138(1-2):123-30. [QxMD MEDLINE Link] .

Trung DT, Thao le TT, Hien TT, et al. Liver involvement associated with dengue infection in adults in Vietnam. Am J Trop Med Hyg . 2010 Oct. 83(4):774-80. [QxMD MEDLINE Link] . [Full Text] .

Potts JA, Rothman AL. Clinical and laboratory features that distinguish dengue from other febrile illnesses in endemic populations. Trop Med Int Health . 2008 Nov. 13(11):1328-40. [QxMD MEDLINE Link] . [Full Text] .

Lima EQ, Nogueira ML. Viral hemorrhagic fever-induced acute kidney injury. Semin Nephrol . 2008 Jul. 28(4):409-15. [QxMD MEDLINE Link] .

Lombardi R, Yu L, Younes-Ibrahim M, Schor N, Burdmann EA. Epidemiology of acute kidney injury in Latin America. Semin Nephrol . 2008 Jul. 28(4):320-9. [QxMD MEDLINE Link] .

Chaterji S, Allen JC Jr, Chow A, Leo YS, Ooi EE. Evaluation of the NS1 rapid test and the WHO dengue classification schemes for use as bedside diagnosis of acute dengue fever in adults. Am J Trop Med Hyg . 2011 Feb. 84(2):224-8. [QxMD MEDLINE Link] . [Full Text] .

Wichmann O, Stark K, Shu PY, Niedrig M, Frank C, Huang JH. Clinical features and pitfalls in the laboratory diagnosis of dengue in travellers. BMC Infect Dis . 2006. 6:120. [QxMD MEDLINE Link] .

Domingo C, de Ory F, Sanz JC, Reyes N, Gascón J, Wichmann O, et al. Molecular and serologic markers of acute dengue infection in naive and flavivirus-vaccinated travelers. Diagn Microbiol Infect Dis . 2009 Sep. 65(1):42-8. [QxMD MEDLINE Link] .

Srikiatkhachorn A, Krautrachue A, Ratanaprakarn W, Wongtapradit L, Nithipanya N, Kalayanarooj S. Natural history of plasma leakage in dengue hemorrhagic fever: a serial ultrasonographic study. Pediatr Infect Dis J . 2007 Apr. 26(4):283-90; discussion 291-2. [QxMD MEDLINE Link] .

Santhosh VR, Patil PG, Srinath MG, Kumar A, Jain A, Archana M. Sonography in the diagnosis and assessment of dengue Fever. J Clin Imaging Sci . 2014. 4:14. [QxMD MEDLINE Link] . [Full Text] .

Srikiatkhachorn A, Gibbons RV, Green S, et al. Dengue hemorrhagic fever: the sensitivity and specificity of the world health organization definition for identification of severe cases of dengue in Thailand, 1994-2005. Clin Infect Dis . 2010 Apr 15. 50(8):1135-43. [QxMD MEDLINE Link] . [Full Text] .

Setiati TE, Mairuhu AT, Koraka P, Supriatna M, Mac Gillavry MR, Brandjes DP, et al. Dengue disease severity in Indonesian children: an evaluation of the World Health Organization classification system. BMC Infect Dis . 2007 Mar 26. 7:22. [QxMD MEDLINE Link] . [Full Text] .

Tassniyom S, Vasanawathana S, Chirawatkul A, Rojanasuphot S. Failure of high-dose methylprednisolone in established dengue shock syndrome: a placebo-controlled, double-blind study. Pediatrics . 1993 Jul. 92(1):111-5. [QxMD MEDLINE Link] .

Wills BA, Nguyen MD, Ha TL, Dong TH, Tran TN, Le TT, et al. Comparison of three fluid solutions for resuscitation in dengue shock syndrome. N Engl J Med . 2005 Sep 1. 353(9):877-89. [QxMD MEDLINE Link] .

Yadav SP, Sachdeva A, Gupta D, Sharma SD, Kharya G. Control of massive bleeding in dengue hemorrhagic fever with severe thrombocytopenia by use of intravenous anti-D globulin. Pediatr Blood Cancer . 2008 Dec. 51(6):812-3. [QxMD MEDLINE Link] .

Waduge R, Malavige GN, Pradeepan M, Wijeyaratne CN, Fernando S, Seneviratne SL. Dengue infections during pregnancy: a case series from Sri Lanka and review of the literature. J Clin Virol . 2006 Sep. 37(1):27-33. [QxMD MEDLINE Link] .

Ismail NA, Kampan N, Mahdy ZA, Jamil MA, Razi ZR. Dengue in pregnancy. Southeast Asian J Trop Med Public Health . 2006 Jul. 37(4):681-3. [QxMD MEDLINE Link] .

Billingsley PF, Foy B, Rasgon JL. Mosquitocidal vaccines: a neglected addition to malaria and dengue control strategies. Trends Parasitol . 2008 Sep. 24(9):396-400. [QxMD MEDLINE Link] .

Erlanger TE, Keiser J, Utzinger J. Effect of dengue vector control interventions on entomological parameters in developing countries: a systematic review and meta-analysis. Med Vet Entomol . 2008 Sep. 22(3):203-21. [QxMD MEDLINE Link] .

Kay B, Vu SN. New strategy against Aedes aegypti in Vietnam. Lancet . 2005 Feb 12-18. 365(9459):613-7. [QxMD MEDLINE Link] .

Hanh TT, Hill PS, Kay BH, Quy TM. Development of a framework for evaluating the sustainability of community-based dengue control projects. Am J Trop Med Hyg . 2009 Feb. 80(2):312-8. [QxMD MEDLINE Link] .

Hoffmann AA, Montgomery BL, Popovici J, Iturbe-Ormaetxe I, Johnson PH, Muzzi F, et al. Successful establishment of Wolbachia in Aedes populations to suppress dengue transmission. Nature . 2011 Aug 24. 476 (7361):454-7. [QxMD MEDLINE Link] .

Lang J. Recent progress on sanofi pasteur's dengue vaccine candidate. J Clin Virol . 2009 Oct. 46 Suppl 2:S20-4. [QxMD MEDLINE Link] .

World Health Organization. Dengue vaccine: WHO position paper – July 2016. Wkly Epidemiol Rec . 2016 Jul 29. 91 (30):349-64. [QxMD MEDLINE Link] .

Aguiar M, Stollenwerk N, Halstead SB. The risks behind Dengvaxia recommendation. Lancet Infect Dis . 2016 Aug. 16 (8):882-3. [QxMD MEDLINE Link] . [Full Text] .

Dengvaxia. European Medicines Agency. Available at https://www.ema.europa.eu/en/medicines/human/EPAR/dengvaxia . 2018 Dec 18; Accessed: April 11, 2023.

Adams LE, Waterman S, Paz-Bailey G. Vaccination for Dengue Prevention. JAMA . 2022 Mar 1. 327 (9):817-818. [QxMD MEDLINE Link] .

Dengvaxia (dengue vaccine) [package insert]. Swiftwater, PA: Sanofi Pasteur, Inc. May 2019. Available at [Full Text] .

Monath TP. Dengue and yellow fever--challenges for the development and use of vaccines. N Engl J Med . 2007 Nov 29. 357(22):2222-5. [QxMD MEDLINE Link] .

Questions and Answers on Dengue Vaccines. World Health Organization. Available at https://www.who.int/immunization/research/development/dengue_q_and_a/en/ . 2018 April 20; Accessed: April 11, 2023.

McArthur JH, Durbin AP, Marron JA, Wanionek KA, Thumar B, Pierro DJ, et al. Phase I clinical evaluation of rDEN4Delta30-200,201: a live attenuated dengue 4 vaccine candidate designed for decreased hepatotoxicity. Am J Trop Med Hyg . 2008 Nov. 79(5):678-84. [QxMD MEDLINE Link] . [Full Text] .

O'Brien J. 12th Annual Conference on Vaccine Research. Expert Rev Vaccines . 2009 Sep. 8(9):1139-42. [QxMD MEDLINE Link] .

Edelman R. Dengue vaccines approach the finish line. Clin Infect Dis . 2007 Jul 15. 45 Suppl 1:S56-60. [QxMD MEDLINE Link] .

Blaney JE Jr, Durbin AP, Murphy BR, Whitehead SS. Development of a live attenuated dengue virus vaccine using reverse genetics. Viral Immunol . 2006 Spring. 19(1):10-32. [QxMD MEDLINE Link] .

Larsen CP, Whitehead SS, Durbin AP. Dengue human infection models to advance dengue vaccine development. Vaccine . 2015 Sep 28. [QxMD MEDLINE Link] .

• Drawing of Aedes aegypti mosquito. Courtesy of the Centers for Disease Control and Prevention (CDC).
• Aedes albopictus. Courtesy of the Centers for Disease Control and Prevention (CDC).
• Worldwide distribution of dengue in 2000. Courtesy of the Centers for Disease Control and Prevention (CDC).
• Worldwide distribution of dengue in 2003. Courtesy of the Centers for Disease Control and Prevention (CDC).
• Worldwide distribution of dengue in 2005. Courtesy of the Centers for Disease Control and Prevention (CDC).
• Increasing rates of dengue infection by regions of the world. Courtesy of the World Health Organization (WHO).
• Dengue transmission cycle. Courtesy of the Centers for Disease Control and Prevention (CDC).
• Reinfestation by Aedes aegypti in the Americas after the 1970 (left) mosquito eradication program and most recent distribution as of 2002 (right). Courtesy of the Centers for Disease Control and Prevention (CDC).
• A child with dengue hemorrhagic fever or dengue shock syndrome may present severely hypotensive with disseminated intravascular coagulation (DIC), as this severely ill pediatric ICU patient did. Crystalloid fluid resuscitation and standard DIC treatment are critical to the child's survival.
• Delayed capillary refill may be the first sign of intravascular volume depletion. Hypotension usually is a late sign in children. This child's capillary refill at 6 seconds was delayed well beyond a normal duration of 2 seconds.
• Signs of early coagulopathy may be as subtle as a guaiac test that is positive for occult blood in the stool. This test should be performed on all patients in whom dengue virus infection is suspected.
• Aedes aegypti mosquito. Courtesy of Wikimedia Commons (https://commons.wikimedia.org/wiki/File:Aedes_aegypti.jpg; author Muhammad Mahdi Karim).
• Global map of dengue risk. Frequent or continuous risk = frequent outbreaks or ongoing transmission. Sporadic or uncertain risk = variable and unpredictable risk, country-level data are unavailable. Courtesy of the Centers for Disease Control and Prevention (CDC) (https://www.cdc.gov/dengue/areaswithrisk/around-the-world.html).

Contributor Information and Disclosures

Darvin Scott Smith, MD, MSc, DTM&H, FIDSA Chief of Infectious Diseases and Geographic Medicine, Department of Internal Medicine, Kaiser Permanente Medical Group Darvin Scott Smith, MD, MSc, DTM&H, FIDSA is a member of the following medical societies: American Medical Association , American Society of Tropical Medicine and Hygiene , Infectious Diseases Society of America , International Society of Travel Medicine Disclosure: Nothing to disclose.

David J Mariano, BS, MS MD Candidate, University of California, San Diego, School of Medicine Disclosure: Nothing to disclose.

Micah Lynne Trautwein, BS MD Candidate, Geisel School of Medicine at Dartmouth Disclosure: Nothing to disclose.

Michael Stuart Bronze, MD David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center; Master of the American College of Physicians; Fellow, Infectious Diseases Society of America; Fellow of the Royal College of Physicians, London Michael Stuart Bronze, MD is a member of the following medical societies: Alpha Omega Alpha , American College of Physicians , American Medical Association , Association of Professors of Medicine , Infectious Diseases Society of America , Oklahoma State Medical Association , Southern Society for Clinical Investigation Disclosure: Nothing to disclose.

Suzanne Moore Shepherd, MD, MS, DTM&H, FACEP, FAAEM Professor of Emergency Medicine, Education Officer, Department of Emergency Medicine, Hospital of the University of Pennsylvania; Director of Education and Research, PENN Travel Medicine; Medical Director, Fast Track, Department of Emergency Medicine Suzanne Moore Shepherd, MD, MS, DTM&H, FACEP, FAAEM is a member of the following medical societies: Alpha Omega Alpha , American Academy of Emergency Medicine , American Society of Tropical Medicine and Hygiene , International Society of Travel Medicine , Society for Academic Emergency Medicine , Wilderness Medical Society Disclosure: Nothing to disclose.

Patrick B Hinfey, MD Emergency Medicine Residency Director, Department of Emergency Medicine, Newark Beth Israel Medical Center; Clinical Assistant Professor of Emergency Medicine, New York College of Osteopathic Medicine Patrick B Hinfey, MD is a member of the following medical societies: American Academy of Emergency Medicine , Wilderness Medical Society , American College of Emergency Physicians , Society for Academic Emergency Medicine Disclosure: Nothing to disclose.

William H Shoff, MD, DTM&H Former Director, PENN Travel Medicine; Former Associate Professor, Department of Emergency Medicine, Hospital of the University of Pennsylvania, University of Pennsylvania School of Medicine William H Shoff, MD, DTM&H is a member of the following medical societies: American College of Physicians , American Society of Tropical Medicine and Hygiene , International Society of Travel Medicine , Society for Academic Emergency Medicine , Wilderness Medical Society Disclosure: Nothing to disclose.

Joseph Domachowske, MD Professor of Pediatrics, Microbiology and Immunology, Department of Pediatrics, Division of Infectious Diseases, State University of New York Upstate Medical University

Joseph Domachowske, MD is a member of the following medical societies: Alpha Omega Alpha , American Academy of Pediatrics , American Society for Microbiology , Infectious Diseases Society of America , Pediatric Infectious Diseases Society , and Phi Beta Kappa

Disclosure: Nothing to disclose.

Hagop A Isnar, MD, FACEP Department of Emergency Medicine, Crouse Hospital

Hagop A Isnar, MD, FACEP is a member of the following medical societies: American College of Emergency Physicians , American Medical Association , and Society for Academic Emergency Medicine

Thomas M Kerkering, MD Chief of Infectious Diseases, Virginia Tech, Carilion School of Medicine, Roanoke, Virginia

Thomas M Kerkering, MD is a member of the following medical societies: Alpha Omega Alpha , American College of Physicians , American Public Health Association , American Society for Microbiology , American Society of Tropical Medicine and Hygiene , Infectious Diseases Society of America , Medical Society of Virginia , and Wilderness Medical Society

Deborah Sentochnik, MD Consulting Staff, Department of Internal Medicine, Division of Infectious Disease, The Mary Imogene Bassett Hospital

Deborah Sentochnik, MD is a member of the following medical societies: American College of Physicians , Infectious Diseases Society of America , and Medical Society of the State of New York

Russell W Steele, MD Head, Division of Pediatric Infectious Diseases, Ochsner Children's Health Center; Clinical Professor, Department of Pediatrics, Tulane University School of Medicine

Russell W Steele, MD is a member of the following medical societies: American Academy of Pediatrics , American Association of Immunologists , American Pediatric Society , American Society for Microbiology , Infectious Diseases Society of America , Louisiana State Medical Society , Pediatric Infectious Diseases Society , Society for Pediatric Research , and Southern Medical Association

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Reference Salary Employment

Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

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Dengue survivors face higher health risks than Covid-19 patients

New research shows that dengue survivors face more long-term health issues than covid-19 survivors..

Listen to Story

• People at a 55% higher risk of heart issues after dengue recovery
• Need preventive measures against dengue to reduce long-term health burdens
• Researchers looked for new health problems that appeared 31 to 300 days after infection

People who recover from dengue are more likely to experience long-term health complications a year later compared to those who had Covid-19, according to researchers at NTU Singapore.

The research revealed that dengue survivors have a 55% higher risk of developing heart issues , such as irregular heartbeats, heart disease, and blood clots, than those who recovered from Covid-19.

The study analyzed data from 11,707 dengue patients and 1,248,326 Covid-19 patients in Singapore between July 2021 and October 2022. Researchers looked for new health problems related to the heart, neurological, and immune systems that appeared 31 to 300 days after infection.

The study's unique comparison was made possible by the circulation of both dengue and Covid-19 during the period .

Published in the Journal of Travel Medicine, the study was conducted by a team from NTU's Lee Kong Chian School of Medicine, the Ministry of Health, Singapore, Singapore General Hospital, the National Centre for Infectious Diseases, and the National Environment Agency.

Dengue is one of the most common vector-borne diseases globally , and the long-term health issues it causes can significantly increase the healthcare burden on both individuals and the country.

Assistant Professor Lim Jue Tao, the study's lead author, explained, "We were motivated to conduct the study due to the increasing geographic range of dengue caused by climate change. We also compared the results with those who recovered from Covid-19, as our previous research suggested a similar risk of long-term health complications."

The study highlights the importance of taking measures to prevent dengue and supports public health planning. Published By: Daphne Clarance Published On: Aug 28, 2024

August 28, 2024

'Sloth Fever' Virus Is Spreading. Here’s What You Need to Know about Oropouche

The Oropouche virus, which causes a disease nicknamed “sloth fever” for one of the animals that can be infected, has seen its first cases in the U.S.

By Mariana Lenharo & Nature News

A C ulex quinquefasciatus mosquito, one of the species in which the Oropouche virus has been found.

gerard lacz/Alamy Stock Photo

Once confined to the Amazon region , the mysterious insect-borne virus that causes Oropouche fever has been expanding its range since late 2023, raising international concern. There have been more than 8,000 confirmed human infections in the Americas so far this year, most of them in Brazil, but Peru, Bolivia, Colombia and Cuba have also been affected.

In July, authorities in Brazil reported the deaths of two adults from the disease — the first fatalities recorded since the virus was identified almost 70 years ago. Brazilian officials are also investigating cases of fetal deaths and malformations that might have been caused by the virus, which investigations have shown can spread from a pregnant person to the fetus. There are no vaccines or treatments for the disease.

Earlier this month, the Pan American Health Organization upgraded its risk level for Oropouche from moderate to high , citing the virus’s geographical spread and the occurrence of fatal cases, which are notable for a disease that has historically been known to cause mild to moderate symptoms. On 23 August, the World Health Organization published a note stating that the public-health risk posed by the virus is high at the regional level and low at the global level. The US Centers for Disease Control and Prevention has advised close surveillance of people returning from affected areas . Cases of Oropouche infection have been identified in people who have travelled to the United States, Spain, Italy and Germany from Brazil and Cuba, including 20 travelers from Cuba to the U.S. that the CDC reported on 27 August.

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Nature spoke to Gonzalo Bello, a public-health specialist at the Oswaldo Cruz Institute in Rio de Janeiro, Brazil, who has studied the lineage of the Oropouche virus currently spreading in the Americas.

What is Oropouche?

Oropouche is a virus of the genus Orthobunyavirus . It differs from other better-known vector-borne viruses like dengue , Zika , yellow fever or Chikungunya because it is typically transmitted to humans by a midge, Culicoides paraensis , rather than by mosquitoes. But we cannot rule out the possibility that other vectors might be involved. [The virus has been found in other insects, including the mosquito Culex quinquefasciatus .]

For how long has this virus been around?

It was discovered in 1955 in Trinidad and Tobago, in the Caribbean. In 1960, it was first detected in Brazil from a blood sample taken from a sloth. Since the 1960s, it has been identified in outbreaks in humans more or less intermittently in the Amazon region [a vast area that spans nine countries in South America]. That’s why we say it’s a re-emerging virus, because it has been circulating for many decades at least in the Amazon, which is considered an endemic region.

Why are we only hearing about it now? Is the current outbreak the biggest so far?

When it comes to the Amazon region, it is difficult to say whether the current outbreak is larger than in previous decades. For the first time, a molecular surveillance diagnostic system is being implemented, something that didn't exist in past epidemics.

The geographic extension of the outbreak does represent a change. The number of municipalities and states affected is much higher. Additionally, the virus has spread outside the Amazon region. Again, we don’t know whether this is the first time because there was no surveillance of Oropouche outside the Amazon before.

What also raises concern is the finding of local transmission in Cuba for the first time. and imported cases in Europe and in the United States. As the Culicoides paraensis midge is found throughout the Americas, from the United States to Argentina, whenever there are infected people and there are vectors, there may be local transmission events. So, any infected individual can generate a local epidemic, that’s the main concern.

What are the symptoms?

The symptoms are similar to those of other arboviruses such as dengue: fever, headache, muscle or joint pain, pain behind the eyes, vomiting and nausea. So it’s very difficult to diagnose an Oropouche infection only from symptoms, you really need to have a molecular laboratory diagnosis. A few cases may evolve into more severe forms, with neurological or hemorrhagic manifestations, but most cases are mild and resolve after seven or eight days.

Is the virus becoming more dangerous? And can it cause microcephaly, an abnormally small head, in babies?

For the first time, the presence of antibodies against Oropouche, indicative of a recent infection, was found in newborns with microcephaly . This suggests an association, but because of the study’s limitations, it wasn’t possible to establish a causal relationship between infection during intrauterine life and the neurological malformations.

But it was possible to establish proof of mother-to-child transmission in cases of fetal and newborn death. In one case, a pregnant woman had symptoms of Oropouche and, weeks later, fetal death was confirmed. The Oropouche genome was detected in several organs of the fetus. In another recent case, a pregnant woman tested positive for Oropouche. The baby was born but died [weeks] later. Post-mortem examination identified the virus genome in various tissues, including the brain.

There were also two deaths of previously healthy young women who had symptoms similar to severe dengue. They were not pregnant. These were the first cases in the literature classified as deaths associated with Oropouche infection.

It is not yet possible to establish how frequently these fatal cases would be happening, either in adults or fetuses. So far, there is no evidence that the symptoms have changed compared with previous outbreaks.

This article is reproduced with permission and was first published on August 26, 2024 .

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An in silico design of a vaccine against all serotypes of the dengue virus based on virtual screening of b-cell and t-cell epitopes.

Simple Summary

Graphical Abstract

1. Introduction

• Conserved Fragments: Identified conserved regions in the viral polyprotein to form the basis of epitope selection;
• ADE Risk Exclusion: Excluded potential ADE-associated epitopes based on a comprehensive literature review;
• Serotype-Specific Epitopes: Combined serotype-specific B-cell epitopes from the E protein with pan-serotype T-cell epitopes from other proteins, including NS1, NS3, NS5, and Capsid;
• Molecule Integration: Integrated all selected epitopes and adjuvant proteins into a single, reasonably sized molecule rather than a complex tetravalent formulation.

2. Materials and Methods

2.1. retrieval and analysis of full-length dengue polyprotein sequences, 2.2. step-by-step selection of epitopes and the estimation of the coverage in the population, 2.2.1. identification of b-cell epitopes.

• Prediction: Continuous B-cell epitopes were predicted in conserved sequences of DENV-1~4 polyproteins using the IEDB database with the Bepipred2.0 method [ 26 ]. It utilizes a hidden Markov model to predict linear B-cell epitopes based on the peptide’s propensity to bind to antibodies. A threshold of 0.5 was set to determine the likelihood of an epitope being immunogenic;
• Selection criteria: Epitopes were first evaluated for their antigenicity (their ability to elicit an immune response) with the online tool VaxiJen [ 27 ], and then intra-serotyped conservancy with the IEDB database to ensure they were preserved within the same serotype of DENV. After that, allergenicity and toxicity were evaluated using Allertop v.2.0 [ 28 ] and Toxinpred [ 29 ] respectively;
• Exclusion of ADE-related epitopes: To mitigate the risk of ADE, relevant literature was collected and utilized to extract the potentially problematic epitopes, detailed in Supplementary Materials Table S11 . ADE-related epitopes were then excluded accordingly from the list of predicted B-cell epitopes, mainly based on their sequence and location in the envelop protein;
• Conservancy analysis: The intra-serotype and cross-serotype conservancy of the epitopes were further analyzed to ensure they were effective across different strains within the same serotypes but not among distinct serotypes. The conservancy analysis was perfumed using the IEDB-based conservancy analysis server [ 30 ].

2.2.2. Identification of CTL and HTL Epitope

• Prediction of epitopes in given length: Epitopes were predicted using NetMHC 4.0 [ 31 ] for CTLs (MHC I) and NetMHC MHC class II 2.3v for HTLs (MHC II) [ 32 ]. These tools predict binding affinities between peptides and MHC molecules, which are critical for T-cell activation. For CTL epitopes, the length was defined as 9 amino acids, while HTL epitopes were considered 15 amino acids. These lengths corresponded to the peptide fragments that can be effectively represented by MHC molecules;
• Binding affinity-based selection of epitopes: Primary selection was conducted based on the binding affinity to MHC I/II receptors, with strong binders (SB) being those in the top <0.5% of the predicted binding scores for both CTLs and HTLs, while weak binders (WB) in the top <2% for either type. This ensured that the selected epitopes had a high likelihood of inducing a strong immune response;
• Further criteria of epitope evaluation: Epitopes with strong binding affinity were further evaluated for their antigenicity, immunogenicity, and intra- and cross-serotype conservancy while ensuring they did not possess characteristics of toxicity or allergenicity.

2.2.3. Population Coverage Analysis

2.3. formulation and evaluation of vaccine candidates.

• B-cell epitopes: A flexible linker sequence, KK, was used to connect B-cell epitopes [ 37 ];
• CTL epitopes: A different flexible linker, AAY, was employed for the connection between CTL epitopes;
• HTL epitopes: A glycine–proline-rich linker, GPGPG, was used to link HTL epitopes;
• Inter-group linkers: A flexible GGGS linker was utilized to join distinct groups of epitopes, ensuring a cohesive antigen structure [ 33 ];
• Adjuvant integration: Adjuvant proteins were conjugated to the N- or C-terminus of the epitope groups via a rigid EAAAK linker.

2.4. Predictions and Validation of Molecular Structure for Vaccine Candidates

2.5. molecular docking and dynamics of the vaccine-immune receptor complexes, 2.6. immune simulation of selected candidate vaccine, 2.7. codon optimization and in silico cloning of selected candidate vaccine, 3.1. conserved fragments were extracted from denv polyprotein sequences collected worldwide, 3.2. effective and non-risky epitopes were selected stepwise from conserved fragments of denv polyprotein for b cells, ctls, and htls, 3.3. three candidate vaccines composed of selected epitopes were predicted as stable, water soluble, and antigenic.

• PSDV-1: Assembling the core antigen with Heparin-binding Hemagglutinin (HBHA) at the N-terminus and beta-defensin at the C-terminus;
• PSDV-2: Assembling the core antigen with HBHA at the N-terminus only;
• PSDV-3: Assembling the core antigen with beta-defensin at the N-terminus only.

3.4. PSDV-2 Was Highlighted for Further Evaluation Based on Structural Advantages and Showed a Tight Interaction with TLRs and HLAs

• Root mean square deviation (RMSD): The RMSD values for either PSDV-2–TLR4 or PSDV-2–TLR2 complexes remained consistently within the allowable range of 4 Å, and reached equilibrium within approximately 40 ns, indicating stable conformational behavior;
• Root mean square fluctuation (RMSF): As a reflection of the flexibility of residues, RMSF values for either complex were stabilized within the permissible 4 Å range, suggesting minimal fluctuations and consistent structural integrity;
• Radius of gyration (Rg): As a measure of the compactness of the protein structure, the Rg value was approximately 37 Å for the PSDV-2–TLR2 complex and 34 Å for the PSDV-2–TLR4 complex, indicating well-maintained structural compactness;
• Hydrogen bonds: The number of hydrogen bonds formed within the TLR receptors remained between 20 and 25 throughout the simulation, highlighting a strong and consistent interaction.

3.5. Robust Responses Were Induced for both Innate and Adaptive Immunity upon the Simulation of the PSDV-2 Candidate Vaccine

3.6. codon optimization and in silico cloning of the designed vaccines, 4. discussion, 5. conclusions, supplementary materials, author contributions, institutional review board statement, informed consent statement, data availability statement, acknowledgments, conflicts of interest.

• Perera, R.; Kuhn, R.J. Structural proteomics of dengue virus. Curr. Opin. Microbiol. 2008 , 11 , 369–377. [ Google Scholar ] [ CrossRef ]
• Pinheiro-Michelsen, J.R.; Souza, R.d.S.O.; Santana, I.V.R.; Da Silva, P.D.S.; Mendez, E.C.; Luiz, W.B.; Amorim, J.H. Anti-dengue vaccines: From development to clinical trials. Front. Immunol. 2020 , 11 , 1252. [ Google Scholar ] [ CrossRef ]
• Xie, Q.; Zhang, B.; Yu, J.; Wu, Q.; Yang, F.; Cao, H.; Zhao, W. Structure and function of the non-structural protein of dengue virus and its applications in antiviral therapy. Curr. Top. Med. Chem. 2017 , 17 , 371–380. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Katzelnick, L.C.; Coello Escoto, A.; Huang, A.T.; Garcia-Carreras, B.; Chowdhury, N.; Maljkovic Berry, I.; Chavez, C.; Buchy, P.; Duong, V.; Dussart, P. Antigenic evolution of dengue viruses over 20 years. Science 2021 , 374 , 999–1004. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Kraemer, M.U.; Sinka, M.E.; Duda, K.A.; Mylne, A.Q.; Shearer, F.M.; Barker, C.M.; Moore, C.G.; Carvalho, R.G.; Coelho, G.E.; Van Bortel, W. The global distribution of the arbovirus vectors Aedes aegypti and Ae. albopictus . Elife 2015 , 4 , e08347. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Gubler, D.J.; Clark, G.G. Dengue/dengue hemorrhagic fever: The emergence of a global health problem. Emerg. Infect. Dis. 1995 , 1 , 55. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Kamath, V.; Aishwarya, A. Dengue vaccines: Current status and future perspectives. APIK J. Intern. Med. 2024 , 33 , 3–15. [ Google Scholar ] [ CrossRef ]
• Thomas, R.; Chansinghakul, D.; Limkittikul, K.; Gilbert, P.B.; Hattasingh, W.; Moodie, Z.; Shangguan, S.; Frago, C.; Dulyachai, W.; Li, S.S. Associations of human leukocyte antigen with neutralizing antibody titers in a tetravalent dengue vaccine phase 2 efficacy trial in Thailand. Hum. Immunol. 2022 , 83 , 53–60. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Thomas, S.J.; Yoon, I.-K. A review of Dengvaxia ® : Development to deployment. Hum. Vaccines Immunother. 2019 , 15 , 2295–2314. [ Google Scholar ] [ CrossRef ]
• Chen, Y.; Huang, A.; Sui, Y.; Tong, X.; Yu, F. Progress and development of three types of live attenuated vaccines for dengue fever. Highlights Sci. Eng. Technol. 2022 , 8 , 497–504. [ Google Scholar ] [ CrossRef ]
• Wilder-Smith, A. Dengue vaccine development by the year 2020: Challenges and prospects. Curr. Opin. Virol. 2020 , 43 , 71–78. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Harapan, H.; Michie, A.; Sasmono, R.T.; Imrie, A. Dengue: A minireview. Viruses 2020 , 12 , 829. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Teo, A.; Tan, H.D.; Loy, T.; Chia, P.Y.; Chua, C.L.L. Understanding antibody-dependent enhancement in dengue: Are afucosylated IgG1s a concern? PLoS Pathog. 2023 , 19 , e1011223. [ Google Scholar ]
• Chan, Y.; Jazayeri, S.D.; Ramanathan, B.; Poh, C.L. Enhancement of tetravalent immune responses to highly conserved epitopes of a dengue peptide vaccine conjugated to polystyrene nanoparticles. Vaccines 2020 , 8 , 417. [ Google Scholar ] [ CrossRef ]
• Sabetian, S.; Nezafat, N.; Dorosti, H.; Zarei, M.; Ghasemi, Y. Exploring dengue proteome to design an effective epitope-based vaccine against dengue virus. J. Biomol. Struct. Dyn. 2019 , 37 , 2546–2563. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Masum, M.H.U.; Ferdous, J.; Lokman, S.; Siddiki, A.Z. Designing of a multiepitope-based chimeric vaccine against dengue virus serotype 3 (DENV-3) through next generation reverse vaccinology approaches. Inform. Med. Unlocked 2024 , 44 , 101422. [ Google Scholar ] [ CrossRef ]
• Saha, O.; Razzak, A.; Sarker, N.; Rahman, N.; Zahid, A.B.; Sultana, A.; Shishir, T.A.; Bahadur, N.M.; Rahaman, M.M.; Hossen, F. In silico design and evaluation of multi-epitope dengue virus vaccines: A promising approach to combat global dengue burden. Discov. Appl. Sci. 2024 , 6 , 210. [ Google Scholar ] [ CrossRef ]
• Alsaiari, A.A.; Hakami, M.A.; Alotaibi, B.S.; Alkhalil, S.S.; Hazazi, A.; Alkhorayef, N.; Jalal, K.; Yasmin, F. Rational design of multi-epitope-based vaccine by exploring all dengue virus serotypes proteome: An immunoinformatic approach. Immunol. Res. 2024 , 72 , 242–259. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Basheer, A.; Jamal, S.B.; Alzahrani, B.; Faheem, M. Development of a tetravalent subunit vaccine against dengue virus through a vaccinomics approach. Front. Immunol. 2023 , 14 , 1273838. [ Google Scholar ] [ CrossRef ]
• Edgar, R.C. MUSCLE: Multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res. 2004 , 32 , 1792–1797. [ Google Scholar ] [ CrossRef ]
• Thompson, J.D.; Gibson, T.J.; Higgins, D.G. Multiple sequence alignment using ClustalW and ClustalX. Curr. Protoc. Bioinform. 2003 , 1 , 2.3.1–2.3.22. [ Google Scholar ] [ CrossRef ]
• Edgar, R.C.; Batzoglou, S. Multiple sequence alignment. Curr. Opin. Struct. Biol. 2006 , 16 , 368–373. [ Google Scholar ] [ CrossRef ]
• Oliver, T.; Schmidt, B.; Nathan, D.; Clemens, R.; Maskell, D. Using reconfigurable hardware to accelerate multiple sequence alignment with ClustalW. Bioinformatics 2005 , 21 , 3431–3432. [ Google Scholar ] [ CrossRef ]
• Saitou, N.; Nei, M. The neighbor-joining method: A new method for reconstructing phylogenetic trees. Mol. Biol. Evol. 1987 , 4 , 406–425. [ Google Scholar ] [ PubMed ]
• Letunic, I.; Bork, P. Interactive Tree of Life (iTOL): An online tool for phylogenetic tree display and annotation. Bioinformatics 2007 , 23 , 127–128. [ Google Scholar ] [ CrossRef ]
• Jespersen, M.C.; Peters, B.; Nielsen, M.; Marcatili, P. BepiPred-2.0: Improving sequence-based B-cell epitope prediction using conformational epitopes. Nucleic Acids Res. 2017 , 45 , W24–W29. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Doytchinova, I.A.; Flower, D.R. VaxiJen: A server for prediction of protective antigens, tumour antigens and subunit vaccines. BMC Bioinform. 2007 , 8 , 4. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Dimitrov, I.; Bangov, I.; Flower, D.R.; Doytchinova, I. AllerTOP v. 2—A server for in silico prediction of allergens. J. Mol. Model. 2014 , 20 , 2278. [ Google Scholar ] [ CrossRef ]
• Gupta, S.; Kapoor, P.; Chaudhary, K.; Gautam, A.; Kumar, R.; Consortium, O.S.D.D.; Raghava, G.P. In silico approach for predicting toxicity of peptides and proteins. PLoS ONE 2013 , 8 , e73957. [ Google Scholar ] [ CrossRef ]
• Calis, J.J.; Maybeno, M.; Greenbaum, J.A.; Weiskopf, D.; De Silva, A.D.; Sette, A.; Keşmir, C.; Peters, B. Properties of MHC class I presented peptides that enhance immunogenicity. PLoS Comput. Biol. 2013 , 9 , e1003266. [ Google Scholar ] [ CrossRef ]
• Andreatta, M.; Nielsen, M. Gapped sequence alignment using artificial neural networks: Application to the MHC class I system. Bioinformatics 2016 , 32 , 511–517. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Nielsen, M.; Lundegaard, C.; Lund, O. Prediction of MHC class II binding affinity using SMM-align, a novel stabilization matrix alignment method. BMC Bioinform. 2007 , 8 , 238. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Fadaka, A.O.; Sibuyi, N.R.S.; Martin, D.R.; Goboza, M.; Klein, A.; Madiehe, A.M.; Meyer, M. Immunoinformatics design of a novel epitope-based vaccine candidate against dengue virus. Sci. Rep. 2021 , 11 , 19707. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Li, W.; Joshi, M.D.; Singhania, S.; Ramsey, K.H.; Murthy, A.K. Peptide vaccine: Progress and challenges. Vaccines 2014 , 2 , 515–536. [ Google Scholar ] [ CrossRef ]
• Jalal, K.; Khan, K.; Ahmad, D.; Hayat, A.; Basharat, Z.; Abbas, M.N.; Alghamdi, S.; Almehmadi, M.; Sahibzada, M.U.K. Pan-genome reverse vaccinology approach for the design of multi-epitope vaccine construct against Escherichia albertii. Int. J. Mol. Sci. 2021 , 22 , 12814. [ Google Scholar ] [ CrossRef ]
• Ghaffari-Nazari, H.; Tavakkol-Afshari, J.; Jaafari, M.R.; Tahaghoghi-Hajghorbani, S.; Masoumi, E.; Jalali, S.A. Improving multi-epitope long peptide vaccine potency by using a strategy that enhances CD4+ T help in BALB/c mice. PLoS ONE 2015 , 10 , e0142563. [ Google Scholar ] [ CrossRef ]
• Dhanushkumar, T.; Kamaraj, B.; Vasudevan, K.; Gopikrishnan, M.; Dasegowda, K.; Rambabu, M. Structural immunoinformatics approach for rational design of a multi-epitope vaccine against triple negative breast cancer. Int. J. Biol. Macromol. 2023 , 243 , 125209. [ Google Scholar ]
• Dimitrov, I.; Flower, D.R.; Doytchinova, I. AllerTOP—A server for in silico prediction of allergens. BMC Bioinform. 2013 , 14 , S4. [ Google Scholar ] [ CrossRef ]
• Hebditch, M.; Carballo-Amador, M.A.; Charonis, S.; Curtis, R.; Warwicker, J. Protein–Sol: A web tool for predicting protein solubility from sequence. Bioinformatics 2017 , 33 , 3098–3100. [ Google Scholar ] [ CrossRef ]
• Magnan, C.N.; Randall, A.; Baldi, P. SOLpro: Accurate sequence-based prediction of protein solubility. Bioinformatics 2009 , 25 , 2200–2207. [ Google Scholar ] [ CrossRef ]
• Gasteiger, E.; Hoogland, C.; Gattiker, A.; Duvaud, S.E.; Wilkins, M.R.; Appel, R.D.; Bairoch, A. Protein Identification and Analysis Tools on the ExPASy Server ; Springer: Berlin/Heidelberg, Germany, 2005. [ Google Scholar ]
• Kaur, H.; Raghava, G.P.S. Prediction of β-turns in proteins from multiple alignment using neural network. Protein Sci. 2003 , 12 , 627–634. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Kelley, L.A.; Mezulis, S.; Yates, C.M.; Wass, M.N.; Sternberg, M.J. The Phyre2 web portal for protein modeling, prediction and analysis. Nat. Protoc. 2015 , 10 , 845–858. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Ramachandran, G.N.; Ramakrishnan, C.; Sasisekharan, V. Stereochemistry of polypeptide chain configurations. J. Mol. Biol. 1963 , 7 , 95–99. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Wiederstein, M.; Sippl, M.J. ProSA-web: Interactive web service for the recognition of errors in three-dimensional structures of proteins. Nucleic Acids Res. 2007 , 35 , W407–W410. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Pettersen, E.F.; Goddard, T.D.; Huang, C.C.; Couch, G.S.; Greenblatt, D.M.; Meng, E.C.; Ferrin, T.E. UCSF Chimera—A visualization system for exploratory research and analysis. J. Comput. Chem. 2004 , 25 , 1605–1612. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Lovell, S.C.; Davis, I.W.; Arendall III, W.B.; De Bakker, P.I.; Word, J.M.; Prisant, M.G.; Richardson, J.S.; Richardson, D.C. Structure validation by Cα geometry: ϕ, ψ and Cβ deviation. Proteins Struct. Funct. Bioinform. 2003 , 50 , 437–450. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Case, D.; Pearlman, D.; Caldwell, J. Amber 18 ; University of California: San Francisco, CA, USA, 2018. [ Google Scholar ]
• Case, D.; Babin, V.; Berryman, J.; Betz, R.; Cai, Q.; Cerutti, D.; Cheatham, T., III; Darden, T.; Duke, R.; Gohlke, H. The FF14SB force field. Amber 2014 , 14 , 29–31. [ Google Scholar ]
• Maier, J.A.; Martinez, C.; Kasavajhala, K.; Wickstrom, L.; Hauser, K.E.; Simmerling, C. ff14SB: Improving the accuracy of protein side chain and backbone parameters from ff99SB. J. Chem. Theory Comput. 2015 , 11 , 3696–3713. [ Google Scholar ] [ CrossRef ]
• Wang, J.; Wolf, R.M.; Caldwell, J.W.; Kollman, P.A.; Case, D.A. Development and testing of a general amber force field. J. Comput. Chem. 2004 , 25 , 1157–1174. [ Google Scholar ] [ CrossRef ]
• Kräutler, V.; Van Gunsteren, W.F.; Hünenberger, P.H. A fast SHAKE algorithm to solve distance constraint equations for small molecules in molecular dynamics simulations. J. Comput. Chem. 2001 , 22 , 501–508. [ Google Scholar ] [ CrossRef ]
• Roe, D.R.; Cheatham, T.E., III. PTRAJ and CPPTRAJ: Software for processing and analysis of molecular dynamics trajectory data. J. Chem. Theory Comput. 2013 , 9 , 3084–3095. [ Google Scholar ] [ CrossRef ]
• DeLano, W.L. Pymol: An open-source molecular graphics tool. CCP4 Newsl. Protein Crystallog. 2002 , 40 , 82–92. [ Google Scholar ]
• Rapin, N.; Lund, O.; Bernaschi, M.; Castiglione, F. Computational immunology meets bioinformatics: The use of prediction tools for molecular binding in the simulation of the immune system. PLoS ONE 2010 , 5 , e9862. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Marques, P.H.; Tiwari, S.; Felice, A.G.; Jaiswal, A.K.; Aburjaile, F.F.; Azevedo, V.; Silva-Vergara, M.L.; Ferreira-Paim, K.; Soares, S.d.C.; Fonseca, F.M. Design of a Multi-Epitope Vaccine against Histoplasma capsulatum through Immunoinformatics Approaches. J. Fungi 2024 , 10 , 43. [ Google Scholar ] [ CrossRef ]
• Grote, A.; Hiller, K.; Scheer, M.; Münch, R.; Nörtemann, B.; Hempel, D.C.; Jahn, D. JCat: A novel tool to adapt codon usage of a target gene to its potential expression host. Nucleic Acids Res. 2005 , 33 , W526–W531. [ Google Scholar ] [ CrossRef ]
• Goldberg, M.F.; Roeske, E.K.; Ward, L.N.; Pengo, T.; Dileepan, T.; Kotov, D.I.; Jenkins, M.K. Salmonella persist in activated macrophages in T cell-sparse granulomas but are contained by surrounding CXCR3 ligand-positioned Th1 cells. Immunity 2018 , 49 , 1090–1102.e7. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Sarker, A.; Dhama, N.; Gupta, R.D. Dengue virus neutralizing antibody: A review of targets, cross-reactivity, and antibody-dependent enhancement. Front. Immunol. 2023 , 14 , 1200195. [ Google Scholar ] [ CrossRef ]
• Naskar, S.; Chandpa, H.H.; Agarwal, S.; Meena, J. Super epitope dengue vaccine instigated serotype independent immune protection in-silico. Vaccine 2024 , 42 , 3857–3873. [ Google Scholar ] [ CrossRef ]
• Diaz, C.; Lin, L.; Martinez, L.J.; Eckels, K.H.; Campos, M.; Jarman, R.G.; De La Barrera, R.; Lepine, E.; Toussaint, J.-F.; Febo, I. Phase I randomized study of a tetravalent dengue purified inactivated vaccine in healthy adults from Puerto Rico. Am. J. Trop. Med. Hyg. 2018 , 98 , 1435. [ Google Scholar ] [ CrossRef ]
• Boigard, H.; Cimica, V.; Galarza, J.M. Dengue-2 virus-like particle (VLP) based vaccine elicits the highest titers of neutralizing antibodies when produced at reduced temperature. Vaccine 2018 , 36 , 7728–7736. [ Google Scholar ] [ CrossRef ]
• Chiang, C.-Y.; Pan, C.-H.; Chen, M.-Y.; Hsieh, C.-H.; Tsai, J.-P.; Liu, H.-H.; Liu, S.-J.; Chong, P.; Leng, C.-H.; Chen, H.-W. Immunogenicity of a novel tetravalent vaccine formulation with four recombinant lipidated dengue envelope protein domain IIIs in mice. Sci. Rep. 2016 , 6 , 30648. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Halstead, S.B. Dengvaxia sensitizes seronegatives to vaccine enhanced disease regardless of age. Vaccine 2017 , 35 , 6355–6358. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Rappuoli, R. Reverse vaccinology. Curr. Opin. Microbiol. 2000 , 3 , 445–450. [ Google Scholar ] [ CrossRef ]
• Pizza, M.; Scarlato, V.; Masignani, V.; Giuliani, M.M.; Arico, B.; Comanducci, M.; Jennings, G.T.; Baldi, L.; Bartolini, E.; Capecchi, B. Identification of vaccine candidates against serogroup B meningococcus by whole-genome sequencing. Science 2000 , 287 , 1816–1820. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Tahir ul Qamar, M.; Bari, A.; Adeel, M.M.; Maryam, A.; Ashfaq, U.A.; Du, X.; Muneer, I.; Ahmad, H.I.; Wang, J. Peptide vaccine against chikungunya virus: Immuno-informatics combined with molecular docking approach. J. Transl. Med. 2018 , 16 , 298. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Hasan, A.; Hossain, M.; Alam, J. A computational assay to design an epitope-based Peptide vaccine against Saint Louis encephalitis virus. Bioinform. Biol. Insights 2013 , 24 , 347–355. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Sarkar, B.; Ullah, M.A.; Johora, F.T.; Taniya, M.A.; Araf, Y. Immunoinformatics-guided designing of epitope-based subunit vaccines against the SARS Coronavirus-2 (SARS-CoV-2). Immunobiology 2020 , 225 , 151955. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Kar, P.P.; Srivastava, A. Immuno-informatics analysis to identify novel vaccine candidates and design of a multi-epitope based vaccine candidate against Theileria parasites. Front. Immunol. 2018 , 9 , 340421. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Chakraborty, S.; Chakravorty, R.; Ahmed, M.; Rahman, A.; Waise, T.; Hassan, F.; Rahman, M.; Shamsuzzaman, S. A computational approach for identification of epitopes in dengue virus envelope protein: A step towards designing a universal dengue vaccine targeting endemic regions. In Silico Biol. 2010 , 10 , 235–246. [ Google Scholar ] [ CrossRef ]
• Friend, U.S.; Parikesit, A.A.; Taufik, R.I.; Amelia, F. In silico analysis of envelope Dengue Virus-2 and envelope Dengue Virus-3 protein as the backbone of Dengue Virus tetravalent vaccine by using homology modeling method. Online J. Biol. Sci. 2009 , 9 , 6–16. [ Google Scholar ]
• Ali, M.; Pandey, R.K.; Khatoon, N.; Narula, A.; Mishra, A.; Prajapati, V.K. Exploring dengue genome to construct a multi-epitope based subunit vaccine by utilizing immunoinformatics approach to battle against dengue infection. Sci. Rep. 2017 , 7 , 9232. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Fahimi, H.; Sadeghizadeh, M.; Mohammadipour, M. In silico analysis of an envelope domain III-based multivalent fusion protein as a potential dengue vaccine candidate. Clin. Exp. Vaccine Res. 2016 , 5 , 41–49. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Tambunan, U.; Parikesit, A. In silico design of drugs and vaccines for dengue disease. Trends Bioinform. 2011 , 4 , 1–9. [ Google Scholar ] [ CrossRef ]
• Gromowski, G.D.; Barrett, N.D.; Barrett, A.D. Characterization of dengue virus complex-specific neutralizing epitopes on envelope protein domain III of dengue 2 virus. J. Virol. 2008 , 82 , 8828–8837. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Rivino, L.; Kumaran, E.A.; Jovanovic, V.; Nadua, K.; Teo, E.W.; Pang, S.W.; Teo, G.H.; Gan, V.C.H.; Lye, D.C.; Leo, Y.S. Differential targeting of viral components by CD4 + versus CD8 + T lymphocytes in dengue virus infection. J. Virol. 2013 , 87 , 2693–2706. [ Google Scholar ] [ CrossRef ]

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Ullah, H.; Ullah, S.; Li, J.; Yang, F.; Tan, L. An In Silico Design of a Vaccine against All Serotypes of the Dengue Virus Based on Virtual Screening of B-Cell and T-Cell Epitopes. Biology 2024 , 13 , 681. https://doi.org/10.3390/biology13090681

Ullah H, Ullah S, Li J, Yang F, Tan L. An In Silico Design of a Vaccine against All Serotypes of the Dengue Virus Based on Virtual Screening of B-Cell and T-Cell Epitopes. Biology . 2024; 13(9):681. https://doi.org/10.3390/biology13090681

Ullah, Hikmat, Shaukat Ullah, Jinze Li, Fan Yang, and Lei Tan. 2024. "An In Silico Design of a Vaccine against All Serotypes of the Dengue Virus Based on Virtual Screening of B-Cell and T-Cell Epitopes" Biology 13, no. 9: 681. https://doi.org/10.3390/biology13090681

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Special report: an orlando police pursuit and fatal crash: the needless death of delmy alvarez, news health, orange dengue cases spark health concerns, response from mosquito control, both cases were contracted locally.

Steve Harrison, mosquito control manager for Orange County Health Services, said the two people infected with the viral fever live in the same household in a community between Orlando and Apopka and contracted the disease locally — meaning they did not travel outside the county, state or U.S. recently.

Dengue is the most common mosquito-borne disease worldwide, and in the worst cases it can be fatal, but only one in four cases are symptomatic.

“The only way for a human to contract dengue is if they are bitten by a mosquito carrying the virus,” Harrison said. “The mosquito can only get the virus by biting a person who has it.

“Fortunately, the mosquito that primarily carries this virus does not fly very far — it stays close to where it originally contracted the virus.”

He said mosquito control is following state health recommendations — targeting control efforts where infections likely occurred. Workers are treating standing water where the flying pests could breed.

Federal health officials warned earlier this summer that risk of contracting dengue in the U.S. had increased as global cases swelled to record numbers. Millions of infections have been reported in Argentina, Brazil and other parts of South America.

The Centers for Disease Control and Prevention, which sent an alert in June to health care providers, reported on its website that most dengue cases in the continental U.S. occur in travelers infected elsewhere and local dengue transmission occurs “occasionally.”

Most infections produce only a mild flu-like illness, but some are severe enough to require hospitalization and can be fatal.

According to CDC, the disease can take up to two weeks to develop and the illness generally lasts less than a week. Symptoms include fever, headache, nausea, vomiting, muscle and joint pain and minor bleeding.

Harrison said dengue is spread by the Aedes aegypti mosquito, which he described as “a daytime biter.”

Zika myths aim to swat mosquito threat

Native to Africa but now common in Florida, the Aedes aegypti mosquito was blamed for spreading Zika virus five years ago. The species has a flight radius of about 200 yards but is believed to have spread worldwide by hitchhiking aboard planes and ships.

State health officials have confirmed 24 other cases in the Orlando area this year, but all were infections in people who traveled outside the area.

According to the CDC, Puerto Rico — classified as having “frequent or continuous” dengue risk — declared a public health emergency in March. The CDC lists the island with more than 2,500 cases this year. Florida is a distant second with about 300 to date.

Harrison suggested residents empty standing water in outside dog dishes, potted plants, birdbaths and other objects that mosquitos can use as breeding grounds. Wearing long sleeves outside and using a repellent can help protect against bites.

Mosquito control regularly sprays for mosquitoes around the county. Its chemicals are approved by the U.S. Environmental Protection Agency and are safe for humans and animals.

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Oropouche Virus Disease Among U.S. Travelers — United States, 2024

Early Release / August 27, 2024 / 73

Andrea Morrison, PhD 1 ; Jennifer L. White, MPH 2 ; Holly R. Hughes, PhD 3 ; Sarah J. Guagliardo, PhD 3 ; Jason O. Velez 3 ; Kelly A. Fitzpatrick, MSPH 3 ; Emily H. Davis, PhD 3 ; Danielle Stanek, DVM 1 ; Edgar Kopp, MS 4 ; Peter Dumoulin, PhD 4 ; Timothy Locksmith, MS 4 ; Lea Heberlein, DrPH 4 ; Rebecca Zimler, PhD 1 ; Joshua Lassen, MPH 1 ; Carolina Bestard, MPH 5 ; Edhelene Rico, MPH 5 ; Alvaro Mejia-Echeverri, MD 5 ; Kay-Anna Edwards-Taylor 6 ; Douglas Holt, MD 6 ; Dionisia Halphen, MPH 7 ; Kaitlynn Peters, MHS 8 ; Cheryl Adams 9 ; Amanda M. Nichols, MPH 10 ; Alexander T. Ciota, PhD 11 ; Alan P. Dupuis II 11 ; P. Bryon Backenson, MS 2 ; Jennifer A. Lehman 3 ; Shelby Lyons, MPH 3 ; Hannah Padda, DVM 3 ,12 ; Roxanne C. Connelly, PhD 3 ; Van T. Tong, MPH 13 ; Stacey W. Martin, MSc 3 ; Amy J. Lambert, PhD 3 ; Aaron C. Brault, PhD 3 ; Carina Blackmore, DVM 14 ; J. Erin Staples, MD, PhD 3 ; Carolyn V. Gould, MD 3 ( View author affiliations )

What is already known about this topic?

Oropouche virus is an emerging arthropod-borne virus in the Americas. Recent reports of outbreaks in areas without previous endemic transmission, fatal cases, and vertical transmission associated with adverse pregnancy outcomes have raised concerns about human health risks.

What is added by this report?

As of August 16, 2024, a total of 21 Oropouche virus disease cases among U.S. travelers returning from Cuba have been reported. Most patients had self-limited illness. At least three patients experienced recurrent symptoms after resolution of the initial illness.

What are the implications for public health practice?

Clinicians and public health jurisdictions should be aware of the occurrence of Oropouche virus disease in U.S. travelers and request testing for suspected cases. Travelers should prevent insect bites when traveling, and pregnant persons should consider deferring travel to areas experiencing outbreaks of Oropouche virus disease.

Beginning in late 2023, Oropouche virus was identified as the cause of large outbreaks in Amazon regions with known endemic transmission and in new areas in South America and the Caribbean. The virus is spread to humans by infected biting midges and some mosquito species. Although infection typically causes a self-limited febrile illness, reports of two deaths in patients with Oropouche virus infection and vertical transmission associated with adverse pregnancy outcomes have raised concerns about the threat of this virus to human health. In addition to approximately 8,000 locally acquired cases in the Americas, travel-associated Oropouche virus disease cases have recently been identified in European travelers returning from Cuba and Brazil. As of August 16, 2024, a total of 21 Oropouche virus disease cases were identified among U.S. travelers returning from Cuba. Most patients initially experienced fever, myalgia, and headache, often with other symptoms including arthralgia, diarrhea, nausea or vomiting, and rash. At least three patients had recurrent symptoms after the initial illness, a common characteristic of Oropouche virus disease. Clinicians and public health jurisdictions should be aware of the occurrence of Oropouche virus disease in U.S. travelers and request testing for suspected cases. Travelers should prevent insect bites when traveling, and pregnant persons should consider deferring travel to areas experiencing outbreaks of Oropouche virus disease.

Investigation and Results

Natural history and clinical symptoms.

Oropouche virus (Simbu serogroup, genus Orthobunyavirus ) is endemic to the Amazon region and was previously identified as a cause of human disease in several countries in South and Central America and the Caribbean ( 1 ). The virus circulates in a sylvatic cycle, possibly involving certain vertebrate hosts (e.g., sloths, nonhuman primates, and birds) and mosquitoes, and an urban cycle in which humans serve as amplifying hosts with known vectors being biting midges ( Culicoides paraensis ) and possibly mosquitoes (e.g., Culex quinquefasciatus ) ( 1 ).

The clinical signs and symptoms of Oropouche virus disease are similar to those of other arboviral diseases such as dengue, Zika, and chikungunya. After an incubation period of 3–10 days, patients typically experience abrupt onset of fever, chills, headache, myalgia, and arthralgia. Other symptoms might include retroorbital pain, photophobia, vomiting, diarrhea, fatigue, maculopapular rash, conjunctival injection, and abdominal pain. Initial symptoms usually last only a few days, but up to 70% of patients are reported to have recurrent symptoms within days to weeks after resolution of their initial illness ( 2 ). Although illness is typically mild, hemorrhagic manifestations (e.g., epistaxis, gingival bleeding, melena, menorrhagia, and petechiae) or neuroinvasive disease (e.g., meningitis and meningoencephalitis) can rarely occur ( 1 , 3 , 4 ). No vaccines to prevent or medicines to treat Oropouche virus disease exist; treatment is supportive.

Recent Outbreaks in South America and Cuba

During December 2023–June 2024, large Oropouche virus disease outbreaks were recognized in areas with known endemic disease, and the virus emerged in new areas in South America and Cuba where it had not been historically reported ( 3 ). As of August 2024, over 8,000 laboratory-confirmed cases have been reported in Bolivia, Brazil, Colombia, Cuba, and Peru ( 3 ). These large outbreaks have resulted in travel-associated cases, with 19 Oropouche virus disease cases in European travelers returning from Cuba (n = 18) and Brazil (one) during June–July 2024 ( 5 ). Recently, cases of severe disease leading to two deaths and vertical transmission associated with fetal death and possible congenital malformations in Brazil have raised concerns about the threat of Oropouche virus to human health ( 3 ).

Identification of U.S. Cases

CDC and New York State Department of Health (NYSDOH) Wadsworth Center conducted Oropouche virus testing for travelers who had returned from areas with known Oropouche virus circulation and had an illness that was clinically compatible with Oropouche virus disease. Clinical diagnostic testing at CDC’s Arboviral Diseases Branch and NYSDOH Wadsworth Center Arbovirus Laboratory is performed using a 90% plaque reduction neutralization test (PRNT 90 ) to detect virus-specific neutralizing antibodies in serum or cerebrospinal fluid, with titers ≥10 considered positive. CDC also conducted surveillance testing on specimens collected ≤7 days after symptom onset using an Oropouche virus real-time reverse transcription–polymerase chain reaction (RT-PCR) assay ( 6 ). This activity was reviewed by CDC, deemed not research, and was conducted consistent with applicable federal law and CDC policy.*

The Florida Department of Health (FLDOH) identified suspected cases primarily by reviewing patients who received negative test results for dengue from state and commercial laboratories and who had a clinically compatible illness and exposure to areas with potential Oropouche virus circulation. Details of epidemiologic investigations, including risk factors, clinical features, and outcomes, are captured from patient interview, clinician interview, or review of medical records using a standardized case investigation form.

Characteristics of U.S. Cases

Evidence of Oropouche virus infection was identified in 21 U.S. residents returning from travel to Cuba, including 20 in Florida and one in New York. Most patients were initially evaluated during their acute illness, but at least three patients were evaluated when their symptoms reoccurred after initial symptom resolution. The median patient age was 48 years (range = 15–94 years) and 48% were female ( Table 1 ). Pregnancy status was not included in this report for reasons of confidentiality. Reported symptoms commenced during May–July and most commonly included fever (95%), myalgia (86%), headache (76%), fatigue or malaise (62%), and arthralgia (57%). Other reported signs and symptoms included diarrhea (48%), abdominal pain (29%), nausea or vomiting (29%), rash (29%), retroorbital pain (24%), back pain (19%), and mucosal bleeding (5%) ( Table 2 ). The combination of fever and myalgia with or without other symptoms was reported in 17 (81%) patients; the combination of fever and headache was reported in 15 (71%). All three symptoms occurred in 13 (62%) patients. Overall, three were hospitalized, and no deaths were reported.

Laboratory evidence of Oropouche virus infection was identified by real-time RT-PCR in 13 patients, by PRNT 90 in seven, and by both assays in one patient. Most real time RT-PCR–positive specimens were collected on days 1–4 (median = 2.5 days; range = 1–7 days) after symptom onset. PRNT 90 –positive specimens were collected a median of 17 days (range = 9–32 days) after symptom onset.

Public Health Response

As a result of the emergence and spread of Oropouche virus in the Americas, CDC is working with state public health jurisdictions and international partners to enable rapid detection and surveillance of Oropouche virus transmission and disease to guide public health prevention measures. CDC is currently developing a plan for rapid detection and response to Oropouche virus disease cases in the United States, assisting health departments with clinical diagnostic and surveillance testing for suspected cases, working to validate a molecular assay to detect acute infections, and updating CDC’s Travelers’ Health notices † and website § on Oropouche as new information becomes available. In addition, CDC is providing clinical consultation and guidance to pregnant persons and their care providers and are tracking the impact of emerging health threats, like Oropouche virus, on pregnant persons and their infants. ¶ Although Oropouche virus disease is not nationally notifiable, CDC encourages jurisdictions to report cases voluntarily to ArboNET, the national arboviral disease surveillance system, using interim case definitions.** For questions about testing or reporting, health departments can contact [email protected] .

The 21 U.S. travel-associated Oropouche virus disease cases were all identified among U.S. residents who had traveled to Cuba. The clinical features of the travelers’ illnesses are similar to those reported in the literature ( 1 , 4 , 7 ). Most patients had a self-limited febrile illness, commonly associated with myalgia and headache with or without additional signs or symptoms, including gastrointestinal symptoms (reported by approximately two thirds of patients). At least three patients initially sought care after experiencing relapse of symptoms following resolution of the initial illness. This reported reoccurrence of symptoms is unique to Oropouche virus disease and is not typically reported in cases of similar arboviral diseases, such as dengue or Zika virus disease ( 2 ). The reoccurrence of symptoms is likely underestimated because of limitations in obtaining a complete clinical history or follow-up after the initial illness.

Among most patients, Oropouche virus disease is mild; however, two deaths in previously healthy young persons with Oropouche virus infection were recently reported in Brazil ( 3 ). In July, the Pan American Health Organization (PAHO) issued an epidemiologic alert concerning possible vertical transmission of Oropouche virus disease associated with adverse pregnancy outcomes, including fetal deaths and congenital malformations ( 3 ).

Clinicians should report suspected Oropouche virus disease cases to state, tribal, local, or territorial health departments to facilitate testing and implementation of community prevention measures and messaging. †† Information for health care providers regarding clinical features, diagnosis, and clinical management are available on CDC’s website. §§ Supportive care is recommended for clinical management of patients. Patients should be advised to avoid nonsteroidal anti-inflammatory drugs to reduce the risk for bleeding. Oropouche and dengue viruses can cocirculate and cause similar symptoms; patients with clinically suspected dengue should be managed according to dengue clinical management recommendations ¶¶ until dengue is ruled out. Interim considerations for clinical management of pregnant persons with Oropouche virus disease and infants born to these pregnant persons are available.***

Oropouche virus disease should be considered in a patient who has been in an area with documented or suspected Oropouche virus circulation ( 3 ) within 2 weeks of initial symptom onset and who experiences an abrupt onset of fever, headache, and one or more of the following: myalgia, arthralgia, photophobia, retroorbital or eye pain, or signs and symptoms of neuroinvasive disease (e.g., stiff neck, altered mental status, seizures, limb weakness, or cerebrospinal fluid pleocytosis). Because patients with Oropouche virus disease can experience reoccurrence of symptoms after resolution of the initial illness, patients might seek care >2 weeks after travel. In suspected Oropouche virus disease cases, testing should be conducted for other diseases with similar symptoms, including dengue, particularly given the recent large dengue outbreak in the Americas with approximately 11 million cases reported since late 2023 ( 8 ). Because of the concern for vertical transmission of Oropouche virus from a pregnant patient to the fetus, paired specimens should be collected from pregnant patients to confirm a recent infection.

Implications for Public Health Practice

Guidance on clinical case identification and management might be modified as the epidemiologic situation evolves, particularly if local transmission in the United States is identified and as more is learned about disease and transmission risk. Based on presently available data, the risk for sustained local transmission in the continental United States is likely low, whereas the risk for sustained transmission in Puerto Rico and U.S. Virgin Islands is unknown. CDC is working with partners to understand more about what is driving the current outbreaks and how that might affect risk of transmission. Vector competence studies are underway to understand the potential role of several U.S. Culicoides spp. of biting midges and mosquito species ( Cx. quinquefasciatus and Aedes aegypti) in Oropouche virus transmission.

Providers should advise persons of the risk for Oropouche virus disease and counsel them to use personal protective measures ††† against mosquito and biting midge bites if traveling to areas with virus circulation. Travelers should use personal protective measures for 3 weeks after return from an area with Oropouche virus circulation, or during the first week of illness in symptomatic patients to prevent further spread, especially in areas where mosquitoes or biting midges are active. Because of the risk for possible vertical transmission providers should inform persons who are pregnant and considering travel to areas with reported Oropouche virus transmission of the possible risks to the fetus. Pregnant travelers should prevent insect bites during travel §§§ and consider deferring travel to areas experiencing outbreaks of Oropouche virus disease. ¶¶¶ CDC is working with PAHO and other partners to learn more about the potential risks associated with infection with Oropouche virus during pregnancy and to increase testing capacity in the region.

Acknowledgments

Amanda Davis, Brittany Rowlette, Katelyn Wolfe, Bureau of Public Health Laboratories, Florida Department of Health; Natalia Cano, Darrell Gibson, Nicadia Gilles, Rayah Jaber, Karina Rivas, Samantha Vaccaro, Bureau of Public Health Laboratories, Florida Department of Health; Kristine Aviles, Nancy Garcia Berwick, Reyna Frias, Erica Louis Jean, Samson Marcellus, Marie France Nicolas, Alan Robles, Doris Rodriguez, Selena Singh, Amelia Pelaez Torres, Karen Velarde, Florida Department of Health in Hillsborough County; Gregory Danyluk, Bernhard Kloppenburg, Florida Department of Health in Polk County; Andres Echeverri, Michelle Persaud, Florida Department of Health in Orange County; Hollie Hall, Renee Halucha, Florida Department of Health in Lee County; Robert Singletary, St. Joseph’s Health Hospital.

Corresponding author: Carolyn V. Gould, [email protected] .

1 Bureau of Epidemiology, Florida Department of Health; 2 Bureau of Communicable Disease Control, New York State Department of Health; 3 Division of Vector-Borne Diseases, National Center for Emerging and Zoonotic Diseases, CDC; 4 Bureau of Public Health Laboratories, Florida Department of Health, Tampa, Florida; 5 Florida Department of Health in Miami-Dade County, Miami, Florida; 6 Florida Department of Health in Hillsborough County, Tampa, Florida; 7 Florida Department of Health in Polk County, Bartow, Florida; 8 Florida Department of Health in Orange County, Orlando, Florida; 9 Florida Department of Health in Lee County, Fort Myers, Florida; 10 Florida Department of Health in Sarasota County, Sarasota, Florida; 11 Arbovirus Laboratory, Wadsworth Center, New York State Department of Health, Slingerlands, New York; 12 Epidemic Intelligence Service, CDC; 13 Division of Birth Defects and Infant Disorders, National Center on Birth Defects and Developmental Disabilities, CDC; 14 Division of Disease Control and Health Protection, Florida Department of Health.

All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Andrea Morrison reports travel support for attendance at meetings from the Council of State and Territorial Epidemiologists (CSTE), the University of Kentucky–Southeastern States Occupational Network, the University of North Carolina, the American Society of Microbiology, and the Infectious Diseases Society of America. Edgar Kopp reports support for travel from the Association of Public Health Laboratories and service on the Association of Public Health Laboratories’ Biosafety and Biosecurity Committee. Joshua Lassen reports support from CSTE. Amanda M. Nichols reports travel and meeting support from the National Association of County and City Health Officials and CSTE. Alexander T. Ciota reports support from the National Institutes of Health. No other potential conflicts of interest were disclosed.

* 45 C.F.R. part 46.102(l)(2), 21 C.F.R. part 56; 42 U.S.C. Sect. 241(d); 5 U.S.C. Sect. 552a; 44 U.S.C. Sect. 3501 et seq.

† https://wwwnc.cdc.gov/travel/notices

§ https://www.cdc.gov/oropouche/about/index.html

¶ https://www.cdc.gov/set-net/about/index.html

** https://www.cdc.gov/oropouche/php/reporting/index.html

†† https://emergency.cdc.gov/han/2024/han00515.asp

§§ https://www.cdc.gov/oropouche/hcp/clinical-overview/index.html

¶¶ https://www.cdc.gov/dengue/hcp/clinical-care/index.html

*** https://www.cdc.gov/oropouche/hcp/clinical-care-pregnancy/index.html ; https://cdc.gov/oropouche/hcp/clinical-care/infants.html

††† https://www.cdc.gov/oropouche/prevention/index.html

§§§ https://www.cdc.gov/mosquitoes/prevention/preventing-mosquito-bites-while-traveling.html

¶¶¶ https://wwwnc.cdc.gov/travel/notices/level2/oropouche-cuba

• Pinheiro FP, Travassos da Rosa AP, Vasconcelos PFC. Oropouche Fever [Section 17]. In: Feigin RD, Cherry JD, Demmler GJ, Kaplan SL, eds. Textbook of pediatric infectious diseases. 5th ed. Philadelphia, PA: Saunders; 2004:2418–23.
• Azevedo RS, Nunes MR, Chiang JO, et al. Reemergence of Oropouche fever, northern Brazil. Emerg Infect Dis 2007;13:912–5. https://doi.org/10.3201/eid1306.061114 PMID:17553235
• Pan American Health Organization, World Health Organization. Epidemiological alert: Oropouche in the Region of the Americas – 1 August 2024. Washington, DC: Pan American Health Organization; Geneva, Switzerland: World Health Organization; 2024. https://www.paho.org/en/documents/epidemiological-alert-oropouche-region-americas-1-august-2024
• Durango-Chavez HV, Toro-Huamanchumo CJ, Silva-Caso W, et al. Oropouche virus infection in patients with acute febrile syndrome: is a predictive model based solely on signs and symptoms useful? PLoS One 2022;17:e0270294. https://doi.org/10.1371/journal.pone.0270294 PMID:35881626
• European Centre for Disease Prevention and Control. Threat assessment brief: Oropouche virus disease cases imported to the European Union. Stockholm, Sweden: European Centre for Disease Prevention and Control, 2024. https://www.ecdc.europa.eu/en/publications-data/threat-assessment-brief-oropouche-virus-disease-cases-imported-european-union
• Naveca FG, Nascimento VAD, Souza VC, Nunes BTD, Rodrigues DSG, Vasconcelos PFDC. Multiplexed reverse transcription real-time polymerase chain reaction for simultaneous detection of Mayaro, Oropouche, and Oropouche-like viruses. Mem Inst Oswaldo Cruz 2017;112:510–3. https://doi.org/10.1590/0074-02760160062 PMID:28591313
• Castilletti C, Mori A, Matucci A, et al. Oropouche fever cases diagnosed in Italy in two epidemiologically non-related travellers from Cuba, late May to early June 2024. Euro Surveill 2024;29:2400362. https://doi.org/10.2807/1560-7917.ES.2024.29.26.2400362 PMID:38940002
• Pan American Health Organization, World Health Organization. PLISA health information for the Americas: dengue. Washington, DC: Pan American Health Organization; Geneva, Switzerland: World Health Organization. Accessed August 14, 2024. https://www3.paho.org/data/index.php/en/mnu-topics/indicadores-dengue-en.html

* Within cells, X = sign or symptom reported; dash = no sign or symptom reported.

Suggested citation for this article: Morrison A, White JL, Hughes HR, et al. Oropouche Virus Disease Among U.S. Travelers — United States, 2024. MMWR Morb Mortal Wkly Rep. ePub: 27 August 2024. DOI: http://dx.doi.org/10.15585/mmwr.mm7335e1 .

MMWR and Morbidity and Mortality Weekly Report are service marks of the U.S. Department of Health and Human Services. Use of trade names and commercial sources is for identification only and does not imply endorsement by the U.S. Department of Health and Human Services. References to non-CDC sites on the Internet are provided as a service to MMWR readers and do not constitute or imply endorsement of these organizations or their programs by CDC or the U.S. Department of Health and Human Services. CDC is not responsible for the content of pages found at these sites. URL addresses listed in MMWR were current as of the date of publication.

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21 cases of little-known Oropouche virus detected in U.S.

The pathogen has garnered headlines in recent weeks with reports of a small number of deaths.

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By Helen Branswell

Aug. 27, 2024

Senior Writer, Infectious Diseases

Nearly two dozen people in the United States have been confirmed to have contracted the Oropouche virus during travels outside the country this summer, the Centers for Disease Control and Prevention reported Tuesday. A previously little-known virus, Oropouche has garnered headlines in recent weeks with reports of a small number of deaths and a possible link to congenital malformations in babies infected in the womb.

All 21 cases — 20 from Florida and one from New York State — were in people who had traveled to Cuba, which is experiencing its first recorded outbreak of Oropouche, sometimes referred to as “sloth fever.” The report was written by public health scientists from Florida and New York and published in the CDC’s online journal Morbidity and Mortality Weekly Report.

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“At this time, we’re currently recommending that pregnant women avoid all non-essential travel to areas with ongoing outbreaks,” Erin Staples, a medical epidemiologist in the CDC’s division of vector-borne diseases, told STAT. Earlier this month, the CDC warned health care providers to be on the lookout for people with Oropouche infections, which have been spreading in several South American countries and Cuba. The European Centre for Disease Prevention and Control also warned doctors in Europe to think about Oropouche when faced with sick travelers, with Spain, Italy, and Germany reporting 19 cases in June and July. Two deaths in Brazil — the first reported in conjunction with Oropouche fever — have been reported, in women in their early twenties. There have also been a handful of reports of the possible vertical transmission of the virus — when a virus is passed from a pregnant person to their fetus — resulting in stillbirths or spontaneous abortions and congenital malformations. In particular, Brazil has reported several babies born with microcephaly — a condition in which the brain is underdeveloped — a finding that is reminiscent of the 2015-2016 Zika outbreak. Investigation of these events is ongoing, according to the Pan American Health Organization, the World Health Organization’s regional operation for the Americas. In an Aug. 3 risk assessment on Oropouche, PAHO indicated it believes there is a high risk of additional spread of the virus, which has triggered a surge of activity in several South American countries so far this year. “The risk of spread could increase due to significant population movements both within and between countries, as well as social, entomological, and environmental factors,” the PAHO assessment warned. 

Until the events of this summer, Oropouche was an obscure virus, gaining little attention outside the areas where it circulates in a cycle that involves birds, sloths, biting insects, and occasionally people. 

You probably have questions about the virus and the disease. STAT has some answers: How is it pronounced?  

Oro-pooosh. Think pooh, but with a “sh” sound tacked on the end. What kind of illness does it trigger? 

About 60% of people who become infected will develop symptoms, which could easily be mistaken for other insect-borne diseases like dengue fever, chikungunya, Zika, or malaria. People who contract Oropouche may experience fever, severe headache, chills, muscle aches, and joint pains. Some may develop sensitivity to light, dizziness, pain behind the eyes, nausea, vomiting, and rash, according to the CDC. 

Staples said a small number of people who contract the virus will develop hemorrhagic symptoms — bleeding gums, for instance — or neuroinvasive illness like meningitis. “Less than 5% of people infected are believed to develop some of these more severe signs and symptoms,” Staples told STAT. Symptoms typically last between two and seven days, but can reoccur after a period of a few days or even weeks, which differentiates Oropouche from some of the other diseases it resembles. Recovery can take days to about a month.

Is there a vaccine? Are there specific drugs?  

In a word, no. The best way not to contract Oropouche is to avoid being bitten by insects.

The CDC told doctors in its alert that rest, fluids, and acetaminophen to control pain and fever can be used to mitigate symptoms. It stressed that aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) shouldn’t be used because they increase the risk of hemorrhagic symptoms. 

When was it discovered? 

The virus gets its name from the area on the island of Trinidad where it was first reported, in 1955. Where is it typically found? 

It is commonly reported in Brazil, especially in the Amazon region. By the end of July, PAHO had been informed of just over 8,000 confirmed cases so far this year, most from Brazil. Other countries that reported transmission included Colombia, Cuba, Bolivia, and Peru. Three-quarters of the cases in Brazil were reported from the Amazon region. How is it transmitted?  Like many of the illnesses it resembles, Oropouche is spread via biting insects — in this case, a species of midges called Culicoides paraensis and a type of mosquito known as Culex quinquefasciatus. Staples cautioned, though, that  it’s unclear whether other midges or mosquitoes can transmit the virus, allowing it to take root in other places. What’s currently known about the virus is how it behaves in the places where it has been studied longest, like the Amazon.

For now, the CDC believes the risk that Oropouche could start to spread in the United States is low — but not zero. “We do know we have some of the same vectors in the Americas that have been described as transmitting it,” Staples said.

In fact, a study published in the journal Viruses in 2021 suggested that midges of a species called Culicoides sonorensis, which is found widely in the United States and parts of Canada, could transmit Oropouche if they became infected.

That said, North American lifestyles could lower the risk the virus poses, Staples said, noting that, during summer when biting insects flourish, people often move from air-conditioned homes to air-conditioned cars.

Like dengue or even West Nile virus, Oropouche virus circulates among some animals and humans. While all the animals that can be infected aren’t known, it’s clear birds, three-toed sloths, and some primates are part of the Oropouche cycle. When bitten by an infected insect, the virus replicates in their blood. When other insects feed on them, it amplifies the amount of virus in a location. At some point, the infection spills over into humans.

About the reporting

STAT’s investigation is based on interviews with nearly 100 people around the country, including incarcerated patients and grieving families, prison officials, and legal and medical experts. Reporter Nicholas Florko also filed more than 225 public records requests and combed through thousands of pages of legal filings to tell these stories. His analysis of deaths in custody is based on a special data use agreement between STAT and the Department of Justice.

You can read more about the reporting for this project and the methodology behind our calculations.

The series is the culmination of a reporting fellowship sponsored by the Association of Health Care Journalists and supported by The Commonwealth Fund.

Helen Branswell

Helen Branswell covers issues broadly related to infectious diseases, including outbreaks, preparedness, research, and vaccine development. Follow her on Mastodon and Bluesky .

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• v.6(1); Jan-Feb 2016

Dengue virus: A global human threat: Review of literature

Shamimul hasan.

Department of Oral Medicine and Radiology, Jamia Millia Islamia, New Delhi, India

Sami Faisal Jamdar

1 Department of Oral and Maxillofacial Surgery, Teerthankar Mahaveer Dental College, Teerthanker Mahaveer University, Moradabad, Uttar Pradesh, India

Munther Alalowi

2 Buraydah College of Dentistry and Pharmacy, Al Qassim, Saudi Arabia

Sadun Mohammad Al Ageel Al Beaiji

3 Department of Conservative Dentistry and Endodontics, Specialist Dental Center, Hafer Al Batin, Saudia Arabia

Dengue is an acute viral illness caused by RNA virus of the family Flaviviridae and spread by Aedes mosquitoes. Presenting features may range from asymptomatic fever to dreaded complications such as hemorrhagic fever and shock. A cute-onset high fever, muscle and joint pain, myalgia, cutaneous rash, hemorrhagic episodes, and circulatory shock are the commonly seen symptoms. Oral manifestations are rare in dengue infection; however, some cases may have oral features as the only presenting manifestation. Early and accurate diagnosis is critical to reduce mortality. Although dengue virus infections are usually self-limiting, dengue infection has come up as a public health challenge in the tropical and subtropical nations. This article provide a detailed overview on dengue virus infections, varied clinical manifestations, diagnosis, differential diagnosis, and prevention and treatment.

INTRODUCTION

The dengue virus, a member of the genus Flavivirus of the family Flaviviridae, is an arthropode-borne virus that includes four different serotypes (DEN-1, DEN-2, DEN-3, and DEN-4).[ 1 , 2 ] The World Health Organization (WHO) consider dengue as a major global public health challenge in the tropic and subtropic nations. Dengue has seen a 30-fold upsurge worldwide between 1960 and 2010, due to increased population growth rate, global warming, unplanned urbanization, inefficient mosquito control, frequent air travel, and lack of health care facilities.[ 3 , 4 , 5 ] Two and a half billion people reside in dengue-endemic regions[ 5 ] and roughly 400 million infections occuring per year, with a mortality rate surpassing 5–20% in some areas.[ 6 ] Dengue infection affects more than 100 countries, including Europe and the United States (USA).[ 7 ] The first reported case of dengue like illness in india was in Madras in 1780, the first virologically proved epidemic of DF in India occurred in Calcutta and Eastern Coast of India in 1963-1964.[ 8 ] Dengue virus infection presents with a diverse clinical picture that ranges from asymptomatic illness to DF to the severe illness of dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS).[ 4 ] Oral mucosal involvement is seen in approximately 30% of patients, although oral features are more frequently associated with DHF than with DF.[ 9 ] Dengue virus infection exhibit varied clinical presentation, hence, accurate diagnosis is difficult and relies on laboratory confirmation. The condition is usually self-limiting and antiviral therapy is not currently available. Supportive care with analgesics, hydration with fluid replacement, and sufficient bed rest forms the preferred management strategy.

ETIOPATHOGENESIS

DF is a severe flu-like infection that involves individuals of all age groups (infants, children, adolescents, and adults).[ 9 ] Transmission among human beings occurs by the mosquito Aedes aegypti and chiefly occurs during the rainy season.[ 10 ] The proposed etiologies for dengue virus infection are:

• Viral replication, primarily in macrophages[ 11 ]
• Direct skin infection by the virus[ 12 ]
• Immunological and chemical-mediated mechanism induced by host–viral interaction.[ 12 ]

Dengue virus gains entry into the host organism through the skin following an infected mosquito bite. Humoral, cellular, and innate host immune responses are implicated in the progression of the illness and the more severe clinical signs occur following the rapid clearance of the virus from the host organism. Hence, the most severe clinical presentation during the infection course does not correlate with a high viral load.[ 13 ] Alterations in endothelial microvascular permeability and thromboregulatory mechanisms lead to an increased loss of protein and plasma. Proposed theories suggest that endothelial cell activation caused by monocytes, T-cells, the complement system, and various inflammatory molecules mediate plasma leakage. Thrombocytopenia may be related to alterations in megakaryocytopoiesis, manifested by infection of human hematopoietic cells and compromised progenitor cell growth. This may cause platelet dysfunction, damage, or depletion, leading to significant hemorrhages.[ 14 , 15 ]

Figure 1 depicts a diagramatic representation of the pathogenesis of dengue.

Pathogenesis of dengue virus infection

CLASSIFICATION

The WHO classifies DF into two groups: Uncomplicated and severe.[ 16 , 17 ] Severe cases are linked to excessive hemorrhage, organ impairement, or severe plasma escape, and the remaining cases are considered uncomplicated.[ 17 ]

According to the 1997 classification, dengue can be divided into undifferentiated fever, DF, and DHF.[ 18 ] DHF was further subdivided into grades I–IV.

Grade I: Only mild bruising or a positive tourniquet test

Grade II: Spontaneous bleeding into the skin and elsewhere

Grade III: Clinical sign of shock

Grade IV: Severe shock - feeble pulse, and blood pressure cannot be recorded.[ 19 ]

Here, grades III and IV comprise DSS.[ 17 ]

CLINICAL MANIFESTATIONS

Undifferentiated fever.

This stage is seen mostly in the primary infection but may also occur following the initial secondary infection. Clinically, it is difficult to differentiate from numerous other viral diseases and often remains undiagnosed.

Dengue fever

DF follows both primary and secondary infections, and is most frequently encountered in adults and older children. Onset of symptoms is characterized by a biphasic, high-grade fever lasting for 3 days to 1 week.[ 20 , 21 ] Severe headache (mainly retrobulbar), lassitude, myalgia and painful joint, metallic taste, apetite loss, diarrhea, vomiting, and stomachache are the other reported manifestations. Dengue is also known as breakbone fever because of the associated myalgia and pain in joints.[ 16 , 22 ] Of patients with DF, 50–82% report with a peculiar cutaneous rash.[ 23 , 24 ] The initial rash is the result of capillary dilatation, and presents as a transient facial flushing erythema, typically occuring before or during the first 1–2 days of fever. The second rash is seen at 3 days to 1 week following the fever, and presents as a asymptomatic maculopapular or morbilliform eruption. Sometimes, individual lesions may merge and present as widespread confluent erythematous areas with pinpoint bleeding spots and rounded islands of sparing, giving a typical appearance of “white islands in a sea of red.”[ 23 , 25 ] The cutaneous rash is usually asymptomatic, and pruritis is reported only in 16-27% cases.[ 9 , 26 ] Bleeding episodes are infrequently seen in DF, although epistaxis and gingival bleeding, substantial menstruation, petechiae/purpura, and gastrointestinal tract (GIT) hemorrhage can occur.[ 20 , 27 ]

Dengue hemorrhagic fever

DHF is frequently seen during a secondary dengue infection. However, in infants it may also occur durring a primary infection due to maternally attained dengue antibodies.[ 28 ] The proposed diagnostic criteria for DHF includes:[ 29 ]

• a. Clinical parameters: Acute-onset febrile phase – high-grade fever lasting from 2 days to 1 week. Hemorrhagic episodes (at least one of the following forms): Petechiae, purpura, ecchymosis, epistaxis, gingival and mucosal bleeding, GIT or injection site, hematemesis and/or malena

Positive tourniquet and hepatomegaly.

• b. Laboratory parameters: Thrombocytopenia (platelet count <100,000/cu mm)

The hemorrhagic episodes in DHF are associated with multifactorial pathogenesis. Vasculopathy, deficiency and dysfunction of platelets and defects in the blood coagulation pathways are the attributed factors.[ 30 ] Decreased production of platelets[ 31 , 32 ] and increased destruction of platelets may result in thrombocytopenia in DHF.[ 33 ] The impaired platelet function causes the blood vessels to become fragile and this results in hemorrhage.[ 34 ]

The clinical course of DHF is characterized by three phases: Febrile, leakage, and convalescent phase. High-grade fever of acute onset along with constitutional signs and facial erythema characterizes the commencement of the febrile illness.[ 21 ] The initial febrile illness is marked by a morbilliform rash and hemorrhagic tendencies.[ 35 ] The fever persists for 2 days to 1 week and then drops to normal or subnormal levels when the patient either convalesces or advances to the plasma leakage phase.[ 36 ] High plasma escape cases are marked by frank shock with low pulse pressure, cyanosis, hepatomegaly, pleural and pericardial effusions, and ascites. Severe ecchymosis and gastrointestinal bleeding followed by epistaxis may also be noted in a few cases. Bradycardia, confluent petechial rashes, erythema, and pallor are seen during this phase.

Dengue shock syndrome

DSS is defined as DHF accompanied by a unstable pulse, narrow pulse pressure (<20 mmHg), restlessness, cold, clammy skin, and circumoral cyanosis. Progressively worsening shock, multiorgan damage, and disseminated intravascular coagulation account for a high mortality rate associated with DSS. The shock persists for a short span of time and the patient promptly recovers with supportive therapy.[ 37 , 38 ]

OROFACIAL FEATURES

Oral features are infrequently seen in dengue virus infection and are more commonly associated with DHF. Erythema, crusting of lips, and ntongue and soft palatal vesicles constitute the prominent oral features in dengue virus infection. Chadwick et al .[ 26 ] reported higher cases involving the mucosa with scleral injection (90%), whereas Sanford noticed vesicular eruptions of the soft palate (>50%).[ 39 ] Byatnal et al ., reported numerous hemorrhagic bullae on the sublingual mucous membrane, lateral surface of the tongue, and floor of the mouth. Brown-colored plaquelike lesions with a rough surface were seen on the buccal mucosa that showed bleeding on touch along with spontaneous bleeding from the gingiva and the tongue. Petechiae, purpura, ecchymoses, and nasal bleeding have also been reported.[ 40 ] Mitra et al . reported bleeding gums, hemorrhagic plaques, and inflamed tonsils in a dengue-infected patient.[ 41 ] Isolated hypoglossal nerve palsy following dengue infection is a rare occurence.[ 42 ] Taste alteration, conjunctival redness, and lymphadenopathy may also be reported in DF.[ 3 ] Table 1 depicts the reported orofacial features of dengue.

Summary of reported orofacial features in dengue[ 4 ]

Cautious attention should be directed at DF if a patient suffers from high fever within 2 weeks of being in the tropics or subtropics.[ 43 ] A decreased number of white blood cells (leukopenia), accompanied by a decreased number of platelet count (thrombocytopenia) and metabolic acidosis are the initial changes on laboratory examinations. Microbiological laboratory testing confirms the diagnosis of DF. Virus segregation in cell cultures, nucleic acid demonstration by polymerase chain reaction (PCR), and serological detection of viral antigens (such as NS1) or particular antibodies are the preferred microbiological assays.[ 5 ] Viral segregation and nucleic acid demonstration provide precise diagnosis, although the high cost limits the availability of these tests.

DIFFERENTIAL DIAGNOSIS

Broad differential diagnosis is considered in a patient presenting with fever and a rash similar to that seen in DF. Tables ​ Tables2 2 and ​ and3 3 present the varied clinical conditions that mimic the febrile and critical phase of dengue infection.

Conditions that mimic the febrile phase of dengue infection[ 4 ]

Conditions that mimic the critical phase of dengue infection[ 4 ]

MANAGEMENT OF DENGUE INFECTION

Fluid replacement and antipyretic therapy with paracetamol is the preferred therapy following the febrile phase. Care should be taken not to use other nonsteroidal antiinflammatory drugs.

Judicious fluid administration forms the mainstay of treatment during the critical phase of the infection. Normal saline, Ringer's Lactate, and 5% glucose diluted 1:2 or 1:1 in normal saline, plasma, plasma substitutes, or 5% albumin are the routinely administered fluids.

WHO guidelines summarize the following principles of fluid therapy:[ 44 ]

• Oral fluid supplementation must be as plentiful as possible. However, intravenous fluid administration is mandatory in cases of shock, severe vomiting, and prostration (cases where the patient is unable to take fluids orally)
• Crystalloids form the first-line choice of intravenous fluid (0.9% saline)
• Hypotensive states that are unresponsive to boluses of intravenous crystalloids, colloids (e.g., dextran) form the second-line measures
• If the patient remains in the critical phase with low platelet counts, there should be a serious concern for bleeding. Suspected cases of bleeding are best managed by transfusion of fresh whole blood.

DENTAL MANAGEMENT

Oral lesions are infrequently seen and are often misguided as platelet defects.[ 25 ] Significant hemorrhagic manifestations need platelet transfusions. In general, there is no need to give prophylactic platelets even at <20,000/cu mm. Prophylactic platelets may be given at a level of <10,000/cu mm in absence of bleeding manifestations. In case of systemic massive bleeding, platelet transfusion may be needed along with red cell transfusion. Liver functions should be monitored.

ADVANCED RESEARCHES

Control of mosquito (vector) transmission, development of dengue vaccine, and antiviral drugs constitute future directions with an aim to prevent and treat dengue infection.

Control of mosquito (vector) transmission can be done by keeping guppies ( Poecilia reticulata ) or copepods ( doridicola agilis ) in standing water, and infecting the mosquito population with bacteria of the Wolbachia genus.[ 43 ]

Due to the progressing transmission and enhancing severity of dengue infection, the necessity to develop a dengue vaccine has gained considerable importance. There is a worldwide public health need for a safe, effective, and economic tetravalent dengue vaccine. Complex pathology, the prerequisite to control four virus serotypes, and inadequate investment by vaccine designers have hindered vaccine advancement.[ 45 ]

Scrupulous attempts are aimed to develop antiviral drugs that can be used to manage DF and avoid the life-threatening episodes.[ 46 , 47 ]

Dengue has evolved as a global life-threatening public health concern, affecting around 2.5 billion individuals in more than 100 countries. The physician should be aware about the varied clinical manifestations of this condition and ensure an early and adequate treatment plan. Future directions to combat this dreadful disease aim at methods of mosquito control, development of vaccine, and antiviral drug regimen.

Financial support and sponsorship

Conflicts of interest.

There are no conflicts of interest.

Disclaimer: Early release articles are not considered as final versions. Any changes will be reflected in the online version in the month the article is officially released.

Volume 30, Number 10—October 2024

Research Letter

Spatiotemporal epidemiology of oropouche fever, brazil, 2015–2024.

Suggested citation for this article

We assessed the spatiotemporal dynamics of Oropouche fever in Brazil during 2015–2024. We found the number of cases substantially increased during that period, particularly in the Amazon region. Our findings underscore the need for improved surveillance and public health measures in response to the disease’s potential spread beyond endemic areas.

Oropouche fever is an emerging arboviral disease caused by Oropouche virus (OROV) and primarily transmitted by Culicoides paraensis biting midges. OROV is endemic to the Americas, predominantly the Amazon region of Brazil; estimates show ≈5 million persons live in areas at high risk for OROV transmission ( 1 ). Despite potential widespread transmission, Oropouche fever has been neglected, and limited data complicate implementation of effective disease control measures. In Brazil, OROV infection has caused numerous outbreaks, particularly in the Amazon region ( 2 ), where the climate and forest environment lead to vector proliferation. In 2024, the Pan American Health Organization and World Health Organization issued alerts of increased cases outside the Amazon ( 3 ) and possible vertical transmission events ( 4 ). Geographic spread affecting both rural areas and densely populated urban centers in non–Amazon region states underscores the virus’ adaptability to varied environments and highlights the urgent need for intensified surveillance and proactive prevention strategies. We assessed the spatiotemporal dynamics of Oropouche fever in Brazil during January 2015–March 2024.

We used anonymized data from the General Coordination of Arbovirus Surveillance of the Ministry of Health (protocol no. 25072.020334/2024-62) and included cases confirmed by reverse transcription PCR or enzyme immunoassay. We extracted information on sex, age, symptom onset, sample collection date, diagnostic method, and location of case notification. We mapped case distributions and calculated cumulative incidence rates per 100,000 inhabitants by using 2022 population census data. We identified high-risk clusters through retrospective spatiotemporal scanning by using SaTScan version 10.1.3 ( https://www.satscan.org ), QGIS version 3.36.3 ( https://qgis.org ), and the discrete Poisson model adjusted for population size. For temporal analysis, we used sample collection dates as reference points, given their enhanced precision and reliability within our dataset. We ran Monte Carlo simulations for significance testing and applied the annual percentage change technique by using Joinpoint Regression Program version 5.0.2 ( https://surveillance.cancer.gov/joinpoint ) to analyze disease incidence trends. We considered p < 0.05 statistically significant in all analyses.

Figure 1 . Spatiotemporal maps of epidemiology of Oropouche fever, Brazil, 2015–2024. A) Cumulative incidence (cases per 100,000 inhabitants); B) high-risk spatiotemporal clusters identified across municipalities. AC, Acre; AL, Alagoas; AM, Amazonas; AP,...

During January 2015–March 2024, Brazil recorded 5,407 Oropouche fever cases; 52% were among male and 48% among female persons. Most (71.4%) cases occurred among persons 20–59 years of age. In total, 18/27 (66.7%) states and 278/5,570 (5%) municipalities reported cases. Among notified cases, 97.1% (5,252 cases) occurred in the Amazon region; only 2.9% (155 cases) were reported outside that area ( Appendix Table 1). Within the Amazon, Amazonas (82.4 cases/100,000 inhabitants), Rondônia (69 cases/100,000 inhabitants), and Acre (42.2 cases/100,000 inhabitants) states had the highest incidence rates. Among non–Amazon region states, Piauí (0.8 cases/100,000 inhabitants) and Bahia (0.7/100,000 inhabitants) had the highest rates ( Figure 1 , panel A).

Figure 2 . Annual cases in a study of spatiotemporal epidemiology of Oropouche fever, Brazil, 2015–2024. Bars depict distribution of cases per year and month of notification; red dotted line shows an analysis...

Spatiotemporal analysis identified 4 major transmission clusters: one across Amazonas, Rondônia, Acre, Roraima, and Mato Grosso starting in 2023; another in Bahia in 2024; a third in Maranhão and Pará in 2021; and a fourth in Pará, Maranhão, and Piauí in 2018 ( Figure 1 , panel B; Appendix Table 2). Temporal analysis also revealed a statistically significant annual increase in incidence of 145.3% (95% CI 76.5%–240.7%) and a sudden rise in reported cases during December 2023–March 2024 ( Figure 2 ).

The first limitation of this study is incomplete travel history data, which might have missed imported cases. Another limitation is potential underdiagnosis, which might have underestimated case numbers. Finally, possible residual or cross-protection immunity could have resulted in uncertainty regarding the at-risk population.

Oropouche fever is predominantly endemic to the Amazon region, where several factors create a favorable scenario for its persistence. The humid and warm climate, complemented by dense vegetation and frequent rainfall, provide ideal conditions proliferation of C. paraensis midges, the primary OROV vector. Concurrently, expansion of human activities, including deforestation and urbanization, modify that vector’s natural habitats, increasing transmission risks by reducing the spaces between humans and vectors ( 1 , 5 , 6 ). Moreover, increasing case numbers in non–Amazon region states might be linked to heightened human mobility and climate changes that extend the geographic distribution of vector habitats. That dynamic could be exacerbated by rapid urbanization without adequate infrastructure, enabling establishment of new urban transmission hotspots ( 7 , 8 ). In addition, potential novel OROV reassortment could enable adaptation to new vectors or enhance virulence, further contributing to expansion to previously unaffected areas (G.C. Scachetti et al., unpub. data, https://doi.org/10.1101/2024.07.27.24310296 ).

Oropouche fever has symptoms similar to other arboviruses, like dengue, which contributes to underreporting and complicates accurate diagnosis ( 9 ). Two Oropouche fever deaths were confirmed in state of Bahia, Brazil, on July 25, 2024 ( https://www.cnnbrasil.com.br/nacional/segunda-morte-por-febre-oropouche-e-confirmada-na-bahia ). Furthermore, recent reports from Pernambuco and Acre documented cases of vertical transmission, mirroring the complex epidemiologic challenges observed during the 2015–16 Zika virus outbreak ( 10 ).

In conclusion, the spatiotemporal dynamics of Oropouche fever in Brazil highlight critical aspects of its epidemiology, particularly its concentration within the Amazon region and statistically significant annual incidence rate increases. Considering the geographic expansion and potential vertical OROV transmission events flagged by the Pan American Health Organization and World Health Organization, this study underscores the pressing need for an integrated surveillance and response system that includes epidemiologic surveillance and public health strategies to effectively manage the expansion of Oropouche fever in Brazil.

Dr. Martins-Filho is an epidemiologist and the head of the Investigative Pathology Laboratory at the University Hospital, Federal University of Sergipe, and holds a research productivity fellowship with the National Council for Scientific and Technological Development (CNPq) in Brazil. His primary research focuses include epidemiology, clinical research, and evidence synthesis.

Acknowledgments

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

P.R.M.F. is a research productivity fellow at the at National Council for Scientific and Technological Development (CNPq), Brazil.

• Romero-Alvarez  D , Escobar  LE , Auguste  AJ , Del Valle  SY , Manore  CA . Transmission risk of Oropouche fever across the Americas. Infect Dis Poverty . 2023 ; 12 : 47 . DOI PubMed Google Scholar
• Mourãão  MP , Bastos  MS , Gimaqu  JB , Mota  BR , Souza  GS , Grimmer  GHN , et al. Oropouche fever outbreak, Manaus, Brazil, 2007-2008. Emerg Infect Dis . 2009 ; 15 : 2063 – 4 . DOI PubMed Google Scholar
• Pan American Health Organization/World Health Organization . Epidemiological alert: Oropouche in the region of the Americas, 9 May 2024. Washington: The Organizations; 2024 .
• Pan American Health Organization/World Health Organization . Epidemiological alert: Oropouche in the region of the Americas: vertical transmission event under investigation in Brazil, 17 July 2024. Washington: The Organizations; 2024 .
• Moreira  HM , Sgorlon  G , Queiroz  JAS , Roca  TP , Ribeiro  J , Teixeira  KS , et al. Outbreak of Oropouche virus in frontier regions in western Amazon. Microbiol Spectr . 2024 ; 12 : e0162923 . DOI PubMed Google Scholar
• Sciancalepore  S , Schneider  MC , Kim  J , Galan  DI , Riviere-Cinnamond  A . Presence and multi-species spatial distribution of Oropouche virus in Brazil within the One Health framework. Trop Med Infect Dis . 2022 ; 7 : 111 . DOI PubMed Google Scholar
• Fonseca  LMDS , Carvalho  RH , Bandeira  AC , Sardi  SI , Campos  GS . Oropouche virus detection in febrile patients’ saliva and urine samples in Salvador, Bahia, Brazil. Jpn J Infect Dis . 2020 ; 73 : 164 – 5 . DOI PubMed Google Scholar
• Sah  R , Srivastava  S , Kumar  S , Golmei  P , Rahaman  SA , Mehta  R , et al. Oropouche fever outbreak in Brazil: an emerging concern in Latin America. Lancet Microbe . 2024 ; 1 : 100904 . DOI PubMed Google Scholar
• Martins-Filho  PR , Soares-Neto  RF , de Oliveira-Júnior  JM , Alves Dos Santos  C . The underdiagnosed threat of oropouche fever amidst dengue epidemics in Brazil. Lancet Reg Health Am . 2024 ; 32 : 100718 . DOI PubMed Google Scholar
• Martins-Filho  PR , Carvalho  TA , Dos Santos  CA . Oropouche fever: reports of vertical transmission and deaths in Brazil. Lancet Infect Dis . 2024 ; S1473-3099(24)00557-7 ; Epub ahead of print . DOI PubMed Google Scholar
• Figure 1 . Spatiotemporal maps of epidemiology of Oropouche fever, Brazil, 2015–2024. A) Cumulative incidence (cases per 100,000 inhabitants); B) high-risk spatiotemporal clusters identified across municipalities. AC, Acre; AL, Alagoas; AM, Amazonas;...
• Figure 2 . Annual cases in a study of spatiotemporal epidemiology of Oropouche fever, Brazil, 2015–2024. Bars depict distribution of cases per year and month of notification; red dotted line shows an...

Suggested citation for this article : Martins-Filho PR, Carvalho TA, dos Santos CA. Spatiotemporal epidemiology of Oropouche fever, Brazil, 2015–2024. Emerg Infect Dis. 2024 Oct [ date cited ]. https://doi.org/10.3201/eid3010.241088

DOI: 10.3201/eid3010.241088

Original Publication Date: August 30, 2024

Table of Contents – Volume 30, Number 10—October 2024

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Paulo Ricardo Martins-Filho, Universidade Federal de Sergipe, Hospital Universitário, Laboratório de Patologia Investigativa, Rua Cláudio Batista, s/n. Sanatório. Aracaju, Sergipe 49060-100, Brazil

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