hypothesis on dengue fever

Dengue Hemorrhagic Fever/Dengue Shock Syndrome

• Symptoms and Signs |
• Diagnosis |
• Treatment |
• Key Points |
• More Information |

Dengue hemorrhagic fever is a variant presentation of dengue infection that occurs primarily in children < 10 years living in areas where dengue is endemic. Dengue hemorrhagic fever, which has also been called Philippine, Thai, or Southeast Asian hemorrhagic fever, frequently requires prior infection with the dengue virus.

Dengue hemorrhagic fever is an immunopathologic disease; dengue virus–antibody immune complexes trigger release of vasoactive mediators by macrophages. The mediators increase vascular permeability, causing vascular leakage, hemorrhagic manifestations, hemoconcentration, and serous effusions, which can lead to circulatory collapse (ie, dengue shock syndrome).

Symptoms and Signs of Dengue Hemorrhagic Fever

Dengue hemorrhagic fever often begins with abrupt fever and headache and is initially indistinguishable from classic dengue. Warning signs that predict possible progression to severe dengue include

Severe abdominal pain and tenderness

Persistent vomiting

Hematemesis

Epistaxis or bleeding from the gums

Black, tarry stools (melena)

Lethargy, confusion, or restlessness

Hepatomegaly, pleural effusion, or ascites

Marked change in temperature (from fever to hypothermia)

Circulatory collapse and multiorgan failure, called dengue shock syndrome, may develop rapidly 2 to 6 days after onset.

Bleeding tendencies manifest as follows:

Usually as purpura, petechiae, or ecchymoses at injection sites

Sometimes as hematemesis, melena, or epistaxis

Occasionally as subarachnoid hemorrhage

Bronchopneumonia with or without bilateral pleural effusions is common. Myocarditis can occur.

Mortality is usually < 1% in experienced centers but otherwise can range to up 30%.

Diagnosis of Dengue Hemorrhagic Fever

Clinical and laboratory criteria

Dengue hemorrhagic fever is suspected in children with World Health Organization–defined clinical criteria for the diagnosis:

Sudden fever that stays high for 2 to 7 days

Hemorrhagic manifestations

Hepatomegaly

Hemorrhagic manifestations include at least a positive tourniquet test and petechiae, purpura, ecchymoses, bleeding gums, hematemesis, or melena. The tourniquet test is done by inflating a blood pressure cuff to midway between the systolic and diastolic blood pressure for 15 minutes. The number of petechiae that form within a 2.5-cm diameter circle are counted; > 20 petechiae suggests capillary fragility.

Complete blood count, coagulation tests, urinalysis, liver tests, and dengue serologic tests should be done. Coagulation abnormalities include

Thrombocytopenia (≤ 100,000 platelets/mcL [≤ 100 x 10 9 /L])

A prolonged prothrombin time (PT)

Prolonged activated partial thromboplastin time (PTT)

Decreased fibrinogen

Increased amount of fibrin split products

There may be hypoproteinemia, mild proteinuria, and increases in aspartate aminotransferase (AST) levels.

Serological diagnosis can be made using the IgM capture enzyme-linked immunosorbent assay (MAC-ELISA). Combined with the dengue virus RNA amplification test, it can provide a diagnosis within the first 1 to 7 days of illness. The plaque reduction neutralization test (PRNT) is specific and sensitive. Titers in acute and convalescent phase serum samples can reliably establish dengue virus infection and may indicate the specific dengue virus type involved. The PRNT requires live dengue viruses for the test and is labor-intensive and expensive. Many laboratories are not able to do the PRNT.

Patients with World Health Organization-defined clinical criteria plus thrombocytopenia ( ≤ 100,000/mcL [≤ 100 x 10 9 /L]) or hemoconcentration (Hct increased by ≥ 20%) are presumed to have the disease (see the Centers for Disease Control and Prevention's Dengue Virus: Clinical Guidance ).

Treatment of Dengue Hemorrhagic Fever

Supportive care

Patients with dengue hemorrhagic fever require intensive treatment to maintain euvolemia. Both hypovolemia (which can cause shock) and overhydration (which can cause acute respiratory distress syndrome) should be avoided. Urine output and the degree of hemoconcentration can be used to monitor intravascular volume.

No antivirals have been shown to improve outcome.

Dengue hemorrhagic fever occurs primarily in children

Dengue hemorrhagic fever may initially resemble classic dengue fever, but certain findings (eg, severe abdominal pain and tenderness, persistent vomiting, hematemesis, epistaxis, melena) indicate possible progression to severe dengue.

Diagnose based on specific clinical and laboratory criteria.

Maintaining euvolemia is crucial.

More Information

The following English-language resource may be useful. Please note that THE MANUAL is not responsible for the content of this resource.

Centers for Disease Control and Prevention: Dengue Virus: For Healthcare Providers : Information on prevention, clinical presentation, diagnosis, and treatment, as well as how to distinguish COVID-19 from dengue

Copyright © 2024 Merck & Co., Inc., Rahway, NJ, USA and its affiliates. All rights reserved.

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February 11, 2010

Scientists prove hypothesis on the mystery of dengue virus infection

by La Jolla Institute for Allergy and Immunology

A leading immunology research institute has validated the long-held and controversial hypothesis that antibodies - usually the "good guys" in the body's fight against viruses - instead contribute to severe dengue virus-induced disease, the La Jolla Institute for Allergy & Immunology announced today. The finding has major implications for the development of a first-ever vaccine against dengue virus, a growing public health threat which annually infects 50 to 100 million people worldwide, causing a half million cases of the severest form.

"Our lab has proven the decades old hypothesis that subneutralizing levels of dengue virus antibodies exacerbate the disease," said La Jolla Institute scientist Sujan Shresta, Ph.D, noting this occurs in people with secondary dengue virus infections who have antibodies to the virus due to a previous infection. "This is a situation where antibodies can be bad for you, which is counter to everything we know about the normal function of antibodies. It also presents a special challenge for researchers working to develop a dengue virus vaccine, since most vaccines work by prompting the body to produce antibodies."

Dengue infection is transmitted by mosquitoes and is caused by any of four closely related virus serotypes of the genus Flavivirus. Infection can cause diseases ranging from dengue fever, a flu-like illness, to the severest form -- dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), which can cause the blood vessels to leak, leading to life-threatening shock. Dengue infection hits hardest in tropical and subtropical areas of Southeast Asia and Latin America.

The dengue virus antibody phenomenon, termed antibody-dependent enhancement of infection (ADE), was first hypothesized in the 1970s by Scott Halstead, M.D., a renowned scientist and one of the world's top experts on dengue virus infection. Dr. Halstead said he got his first inkling of the phenomenon while doing extensive clinical studies of dengue virus patients in Thailand in the 1960s. "We were able to detect that the severe patients all had a secondary antibody response, meaning that they had all been infected before," he said. "That was the first evidence we had that a person had to have a previous dengue infection to get the severe disease." Further epidemiological observations, including cases in which severe dengue virus occurred in infants born to previously infected mothers, along with lab cell studies, prompted Dr. Halstead to put forth the ADE hypothesis. Dr. Shresta's work, conducted in mouse models, provides the first in vivo proof of ADE's occurrence.

Dr. Halstead said he is pleased to see his hypothesis proven in animal studies, but actually finds Dr. Shresta's development of a solid dengue virus mouse model even more exciting. Dr. Shresta is credited with developing the world's first mouse model showing key aspects of human infection.

"A model like this is really a breakthrough in tools," said Dr. Halstead, who is research director for the Pediatric Dengue Vaccine Initiative at the International Vaccine Institute, Seoul, Korea and a consultant to the Rockefeller Foundation in New York. "We've been looking for 40 years for a model to be able to test this (ADE) phenomenon. It will allow us to study the virus and the antibody enhancement in ways never before possible."

Using the mouse model, the Shresta group has already made a key and surprising observation that a type of liver cells, called liver sinusoidal endothelial cells (LSCEs), but not the previously expected cells types (such as macrophages and dendritic cells) support ADE of dengue infection.

Scientists had long complained that the lack of a good animal model hampered efforts to develop a first-ever dengue vaccine. Dr. Shresta said her group's ADE findings emphasize the importance of special caution in designing a dengue virus vaccine. "Researchers will have to be extremely careful to ensure that, under no conditions, will a dengue vaccine generate these subneutralizing antibody conditions," she said. "Otherwise, it could cause people to develop the severest and potentially lethal form of the disease -- dengue hemorrhagic fever/dengue shock syndrome."

Dr. Halstead agreed and said efforts should focus on a vaccine that protects against all four serotypes to avoid subsequent infections. "The vaccine should cause you to make antibodies to each of the four dengue viruses," he said, noting that he is working with several groups using this approach. "That's what makes it difficult; you have to make four vaccines in one. The kind of model Dr. Shresta has done will be important as researchers work to develop a vaccine."

Dr. Shresta's findings were published online today in Cell Host & Microbe in her paper entitled, "Enhanced Infection of Liver Sinusoidal Endothelial Cells in a Mouse Model of Antibody-Induced Severe Dengue Disease."

Dr. Shresta said the fact that dengue viruses exist as four different serotypes that circulate simultaneously underlies the development of the subneutralizing antibodies. Infection with one of these serotypes provides lifelong immunity to the infecting serotype only. In subsequent dengue infections, where a different serotype of the virus is involved, the antibodies do not recognize enough of the virus to neutralize it. "This starts a cascade of unusual molecular events - the ADE process -- which leads to the antibodies contributing to, rather than fighting, the dengue infection," she said.

The World Health Organization (WHO) estimates that about 2.5 billion people, or 40% of the world's population, live in areas where there is a risk of dengue transmission. About 500,000 cases of dengue's severest form (DHF/DSS) occur annually, resulting in about 24,000 deaths, mostly among children. Tropical and subtropical areas of Southeast Asia and Latin America are hardest hit by dengue infection. Although dengue rarely occurs in the continental United States, it is endemic in Puerto Rico, a U.S. territory. Mosquitoes capable of transmitting the virus have been found in the U.S. over the last 10 years.

Provided by La Jolla Institute for Allergy and Immunology

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The Complexity of Antibody-Dependent Enhancement of Dengue Virus Infection

Antibody-dependent enhancement (ADE) has been proposed as a mechanism to explain dengue hemorrhagic fever (DHF) in the course of a secondary dengue infection. Very recently, Dejnirattisai et al. , 2010 [ 1 ], published an important article supporting the involvement of anti-prM antibodies in the ADE phenomenon. The complexity of ADE in the context of a secondary dengue infection is discussed here.

1. Introduction

A rapid increase in dengue reports has been observed in the last three decades. Today, dengue infections are a serious cause of morbidity and mortality in most tropical and subtropical regions of the world: an estimated 50–100 million people are infected annually and over 2.5 billion people live in endemic areas; and more than 100 countries are at risk for dengue transmission. The disease is endemic in Asia, the Pacific, the Americas, Africa and the Middle East [ 2 , 3 ].

Dengue is caused by four antigenically related viruses (DENV 1–4) within the family Flaviviridae , genus Flavivirus . These are transmitted to humans by Aedes mosquito bites, and Aedes aegypti is the main vector. The genome of these enveloped single-strand positive-polarity RNA viruses codes for three structural proteins (capsid C, membrane, M, and the envelope, E) and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5) [ 4 ].

Two types of virions are recognized: mature extracellular virions contain M protein, while immature intracellular virions contain prM, which is proteolytically cleaved during maturation to yield M protein.

The envelope of the virus contains the viral surface proteins E and M. The E glycoprotein has important functional roles in virus attachment to cells and fusion with membranes, and is the major target for neutralizing antibody. It contains the main epitopes recognized by neutralizing antibodies (virus-specific and cross-reactive epitopes) [ 5 , 6 ]. This protein has three structural and functional domains: domain II contains the internal fusion peptide (responsible for the fusion of flaviviruses to their target cells) and domain III the cellular receptor-binding motifs [ 7 , 8 ]. Domains I and III contain predominantly subcomplex- and type-specific epitopes, whereas domain II contains the major flavivirus group and subgroup cross-reactive epitopes [ 9 – 11 ].

M protein may be found in two forms. In cell-associated (immature) virions, prM (the precursor of M protein) is observed, which forms a heterodimer with the E protein (prM-E heterodimer). Apparently, prM serves as a chaperone for the E protein, protecting it from irreversible inactivation during transport of virions to the cell surface in acidic post-Golgi vesicles [ 12 , 13 ]. Through this association, prM participates in the viral assembly and budding into the lumen of the endoplasmic reticulum. Intracellular virions remain non-infectious until release when they are converted to infectious form through the cleavage of prM into the soluble pr peptide and the particle associated M protein by a host-cell-derived furin-like protease [ 14 ].

Uncleaved prM prevents the E protein from undergoing the structural changes that are required for low-pH-induced membrane fusion of DENV. Therefore, fully immature DENV is essentially non-infectious [ 15 ]. Depending on the extent of prM cleavage, the extracellular particles may contain varying proportions of prM and M. Levels of around 30% of prM containing immature particles have been reported in DENV infected cells [ 16 , 17 ]. The charged residues surrounding the furin consensus sequence at the prM cleavage junction could partially explain lower or higher cleavage efficiency; in addition, structural differences inherent to flaviviruses at prM junction affect prM cleavability [ 18 ].

2. Dengue Hemorrhagic Fever, Secondary Infection and Antibody-Dependent Enhancement

Dengue infection can be asymptomatic or present in two clinical forms of illness, dengue fever (DF) and the more severe dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). Plasma leakage, hemorrhage and thrombocytopenia characterize DHF/DSS [ 19 , 20 ].

Single-serotype natural infections result in lifelong immunity to the infecting serotype but only short-term cross-protection against heterotypic serotypes [ 21 ]. The humoral response to dengue infection is important for controlling infection and virus dissemination. Despite antigenic relatedness of viruses in the dengue complex, two or more serotypes may sequentially infect one individual. Specific neutralizing IgG antibody against the infecting DENV lasts decades, while cross-reactive neutralizing activity declines over time [ 22 , 23 ]. Preliminary reports also suggest that in human beings there is a continuous selection process of populations of dengue-virus neutralizing-antibodies with increasing homologous reactivity and concurrent decrease in heterotypic cross reactions [ 24 ].

Early studies in Thailand recognized that DHF/DSS peaked in two populations: first-time infected infants born to dengue-immune mothers and children who had experienced a mild or asymptomatic dengue infection and become secondarily infected by a different dengue serotype [ 25 , 26 ]. These studies suggested that DHF/DSS is 15–80 times more frequent in secondary infections than in primary ones, and that up to 99% of DHF cases reveal heterotypic antibodies to the dengue serotype causing the DHF [ 27 ].

These first observations were confirmed in a different setting. The DENV 2 epidemic of 1981 (preceded by a mild epidemic of DENV 1 in 1977) reported in Cuba, supported secondary infection as a main risk factor for the severe forms of dengue infection. In this epidemic of more than 300,000 cases, 10,000 severe and very severe cases and 158 fatalities (101 children), secondary infection in the sequence DENV 1/DENV 2 was demonstrated in 98% of the DHF/DSS cases [ 28 – 30 ]. In addition, DHF/DSS did not occur in children of 1–2 years. They were born after the 1977 epidemic and, consequently, in 1981, they were at risk only of primary DENV infection [ 29 ]. More than 20 years after the DENV 1 epidemic, secondary infection as a main risk factor for DHF/DSS was confirmed again in the Cuban epidemics of 1997 (DENV 2) and 2001–02 (DENV 3) [ 31 – 35 ].

To explain the association of secondary infection to severe illness, Antibody-Dependent Enhancement (ADE) was proposed as the immune system’s mechanism to enhance viral pathogenesis. ADE has been described for several viruses including DENVs, measured by in vitro enhancement of cell infection [ 36 – 38 ]. Also, monkeys passively immunized concurrently with a DENV infection developed a higher viremia than control animals [ 39 ]. More recently, Goncalvez et al. [ 40 ] demonstrated a significant increase of DENV 4 viremia titers in monkeys passively immunized with transferred dilutions of an anti-dengue humanized monoclonal antibody [ 40 ].

In humans, indirect evidence of ADE has been reported. ADE was observed in vitro in sera from mothers whose infants developed DHF after a primary dengue infection [ 41 ]. This study demonstrated that maternal antibody to DENV declines at a constant rate and passes in time through three functional states: neutralization, enhancing virus growth and antibody degradation. This early study suggested that as anti-dengue antibody to a first infection wanes, some individuals will experience an interval during which their antibody level will drop below its protective capacity, acquiring the power to enhance infection. In another study, Kliks et al. [ 42 ] reported that undiluted pre-infection sera from children who developed DHF were more likely to show enhancement of the dengue virus infection than pre-infection sera of children with an asymptomatic secondary infection.

Evidence suggests that enhancing and cross-reactive neutralizing antibodies regulate dengue epidemics and disease severity. In this sense, epidemiological and serological observations made during the Cuban dengue epidemics support the role of secondary infection and ADE even 20 or more years after primary dengue infection. A marked increase in severity associated with the longer of the two intervals (20 years versus four years) between an initial DENV1 infection and a secondary DENV 2 (Asian genotype) infection has been reported [ 43 ]. In addition, some sequences of infection such as DENV 1 followed by DENV 2, and DENV 1 followed by DENV 3 have been associated with greater disease severity [ 44 , 45 ].

3. The Antibody-Dependent Enhancement Phenomenon

ADE occurs when antibody-virus complexes are internalized into cells via FcγRs resulting in infection of a higher number of target cells, which may lead to higher viral production. Cross-reactive antibodies lacking neutralizing activity are induced during a primary dengue infection. In secondary infection, these antibodies bind to the second infecting virus. Increased viral production has typically been interpreted to be the result of an increased number of infected Fcγ-R-bearing cells and possibly the result of an accelerated rate of internalization and cell infection by immune-complexes [ 46 – 48 ]. A higher viremia in infected patients and consequent greater severity has been hypothesized [ 49 ]. Studies reported by Vaughn et al. and Libraty et al. observed a higher viremia and NS1 antigenemia in children with DHF than in those with DF [ 50 , 51 ]. Also in Taiwanese patients it was observed that dengue RNA titers even after defervescence, correlated with disease severity [ 52 ]. In a more recent study, Cameron et al. reported heterogeneity in viremia and NS1 antigenemia in Vietnamese infants with DHF in the course of their primary DENV infection; however these determinations were made at the time of hospital admission. They also found that these infants experienced DHF when the maternally-derived neutralizing antibody titer had declined to <1:20 [ 53 ].

A complementary mechanism to higher viremia explaining disease severity as a consequence of ADE may be that FcγR-mediated entry suppresses the antiviral immune response. An in vitro study with Ross River virus showed that viral entry via the FcR pathway could suppress antiviral genes and enhance IL-10 production, while entry via the normal mechanism does not change the antiviral environment [ 54 ]. In the case of dengue, it has been reported that infection of THP-1 cells via FcR also suppresses transcription and production of IL-12, IFNγ, TNFα and NO, but enhances the expression of anti-inflammatory cytokines [ 55 ] with a milieu change favorable to viral replication. These observations suggest that ADE of DENV infection not only facilitates the virus entry process but also could modify innate and adaptive intracellular antiviral mechanisms [ 55 ].

Studies using monoclonal antibodies have demonstrated that enhancing antibodies are directed to E and prM proteins [ 56 ]. Although both proteins seem to be involved in neutralization and the ADE mechanism, more studies have been designed to evaluate the role of E protein. Greater understanding of the antibody-neutralization mechanisms could shed light on their likelihood of promoting ADE.

4. The Neutralization Mechanism

Flavivirus neutralization is a multiple-hit phenomenon requiring engagement by more than one antibody. Neutralization occurs when the number of antibodies bound to an individual virion exceeds a required threshold, antibody affinity and accessibility of epitopes on virus particles playing an important role [ 57 ]. Neutralizing antibodies directed mostly to E protein inhibit viral attachment, internalization and/or replication within the cell [ 58 ]. These E-specific antibodies appear to be pivotal, mediating homologous protection against dengue reinfection; however, in mice, prM vaccine has also been shown to protect against the lethal DENV challenge [ 59 ].

Neutralization at low occupancy requires lower antibody concentrations and can occur with lower-affinity antibodies, while those antibodies specific to poorly accessible epitopes require relatively high concentrations. Most epitopes have the capacity to elicit antibodies capable of promoting ADE [ 60 ]; however, antibodies specific to poorly accessible epitopes are more likely to promote ADE over a wide range of concentrations [ 61 , 62 ]. Recently, Lok et al. [ 63 ] showed that a partially occluded epitope may become available to antibody binding under certain conditions, suggesting that the virus is in dynamic motion making hidden epitopes briefly available [ 63 ].

Despite the large body of work with mouse monoclonal antibodies, little has been done to characterize the binding properties of human dengue immune sera and to understand the relationship between human antibody binding, neutralization and ADE [ 64 ]. Recent studies have proposed that the major cross-reactive and serotype-specific neutralizing epitopes targeted by human immune sera are inter-domain epitopes and/or located outside of domain III of E protein [ 40 , 65 ]. Wahala et al. observed that, unexpectedly, domain III-binding antibodies play a minor role in DENV neutralization. In addition, in another report these authors suggest that type-specific epitopes on domain III are not conserved between strains of DENV3 [ 66 ]. Previous investigations support large differences in neutralization titers when comparing different genotypes of the same virus [ 67 , 68 ].

5. Potential Role of Immature DENV in Antibody-Dependent Enhancement

Recently, Dejnirattisai et al. [ 1 ] generated a panel of human monoclonal antibodies to DENV. They observed that (a) antibodies to prM were a major component of the response, highly cross-reactive among the dengue serotypes, and (b) these antibodies have potent ADE activity and low neutralization capacity. Considering these results, the authors propose that partial cleavage of prM reduces antigen density availability for viral neutralization, leaving the viruses susceptible to ADE by antibody to prM.

Previously, a host-protective effect of anti-prM was reported for DENV; however, how these antibodies would exert their effect was not clear [ 18 , 59 , 69 – 71 ]. It has been proposed that weak neutralization of dengue infectivity by some anti prM monoclonal antibodies and anti-prM peptide sera could be due to their cross-reactivity with E protein [ 18 , 70 , 71 ]. However, similar levels of enhancing activity by strongly enhancing anti-E monoclonal antibodies have been previously reported [ 56 , 72 ]. Some studies report enhancement of infection presumably due to the presence of uncleaved prM in virus preparations, but also with DENV particles containing high levels of prM after cell treatment with chloroquine [ 72 , 73 ]. Apparently, infection enhancement and lack of potent neutralization are common properties of anti-prM antibodies, suggesting that prM constitutes another target for infection-enhancing antibodies but also that extracellular dengue virions containing prM could be infectious [ 18 ].

Previous studies have shown that immature particles are non-infectious, since the presence of prM obstructs the low-pH-induced conformational changes in the E protein required for membrane fusion of the virus [ 15 , 74 ]. However, very recently, Rodenhuis-Zybert et al. [ 75 ] showed that fully immature dengue particles become highly infectious when interacting with prM antibodies. They showed that lack of infectivity of immature particles in the absence of antibodies was related to inefficient binding of immature virions to cell surfaces, but if binding is facilitated through anti-prM antibodies, immature particles become highly infectious, presumably due to efficient intracellular processing of prM to M by furin activity within the target cell. These antibodies facilitate efficient binding and cell entry by immature particles into Fc-R- expressing cells [ 75 ].

Together, these observations suggest that immature viral particles have the potential to be highly infectious and hence may contribute to development of the severe disease during secondary infection [ 75 ]. Consequently, it is important to define the possible in vivo effects of maintaining prM on the virion surface but also the viral and host factors involved in the efficiency of prM cleavage. It has been suggested that alteration of furin target sequence in the prM junction can affect virus export [ 76 ]. Also, several studies have suggested that the multiplication of flaviviruses is not self-reliant and that the viruses subvert cellular proteins to become part of their replication strategy [ 77 , 78 ].

Of interest is that Dejnirattisai et al. [ 1 ] found that antibodies to prM were a major component of the anti-dengue response. Previous reports recognized that the main response is directed to E protein, but also support that anti-prM antibodies are generated during dengue infection in humans [ 79 – 81 ]. It cannot be excluded that these apparently dissimilar observations depend on the characteristics of the tested samples and the employed methodologies.

CryoEM images have shown that WNV and DENV preparations contain a mixture of immature, partially mature and mature viral particles, most likely due to incomplete processing by furin during maturation [ 82 ]. Cherrier et al. showed that an epitope within the fusion loop of WNV E protein is largely inaccessible in mature virions but that a cross-reactive fusion-loop antibody with low neutralization activity binds preferentially to the spikes in immature virions [ 82 ]. In a secondary infection, these antibodies may promote infection through ADE by augmenting attachment and/or entry of partially immature virions. The fact that an antibody neutralizes infectivity by binding to an immature virion supports the hypothesis that hybrid mature/immature particles can contribute to virus infectivity and pathogenesis [ 82 ]. These observations can also be extended to anti prM antibody.

Figure 1 shows viral populations and anti-E and -prM antibodies involved in neutralization and ADE of DENV infection.

6. Conclusions

DHF/DSS is the result of the interaction of several factors in which the viral and host characteristics are important [ 44 , 83 ]. Some DENV genotypes have the potential to produce DHF [ 84 ]. In addition, host factors are of importance: these include age (children at higher risk than adults), ethnicity (white people at higher risk than black people), chronic diseases (bronchial asthma, diabetes mellitus, sickle cell anemia), nutritional status, sex and the individual’s genetic composition (allelic variants of genes that encode cellular receptors such as DC-SIGN and FcγRIIA, Vitamin D receptor as well as molecules involved in the antigen recognition, HLA, and cytokines have also been associated with higher or lower risk of DHF) [ 85 – 91 ]. However, secondary infection is considered the main risk factor for disease severity.

The dengue antibody somehow modulates subsequent infection with an enhancing or neutralizing role that up- or down-regulates dengue infection of mononuclear phagocytes ( Figure 1 ) [ 92 ]. Consistent with current evidence and considering ADE as a central mechanism, a working hypothesis of dengue pathogenesis suggests that DHF/DSS during a secondary infection is the result of antibody-enhanced infection of mononuclear phagocytes. Immune complex infection suppresses cellular immune responses, increasing intracellular infection and generating inflammatory cytokines and chemokines that together contribute to the development of severe disease [ 48 ].

Concern over ADE and its role in DHF/DSS suggest the necessity of a tetravalent dengue vaccine stimulating a balanced and long-lasting immune response to the four serotypes. The elegant work published by Dejnirattisai et al. [ 1 ] adds new information to our knowledge about ADE, calling attention to the complexity of this phenomenon [ 1 ]. More research is needed to elucidate ADE’s molecular mechanisms, particularly factors influencing the final outcome of the interaction among the virus, antibody and permissive cells. Among the issues meriting careful study are the interaction of anti-prM and -E antibodies with the infecting virus to neutralize or enhance infection, the factors determining the ratio of immature/mature virion particles, the influence of ADE complement levels, and the interaction with Fc-receptors [ 93 – 96 ].

Acknowledgments

The authors thank Gail Reed, Didye Ruiz and Olaf Horstick for their technical support as well as J.M. Smit for her useful comments and suggestions.

References and Notes

This page has been archived and is no longer updated

Current Dengue Fever Research

Introduction, basic research on dengue.

What does basic dengue research involve? Basic research includes a wide range of studies focused on learning how the dengue virus is transmitted and how it infects cells and causes disease. This type of research investigates many aspects of dengue viral biology, including exploration of the interactions between the virus and humans and studies of how the dengue virus replicates itself.

One important field of basic research is dengue pathogenesis , the study of the process and mechanisms of dengue in humans. Scientists want to understand how the dengue virus causes damage to the human body and how the immune system responds to a dengue infection so that they can develop new treatments for the disease. For example, researchers want to understand why bleeding and vascular leakage occur in patients with severe dengue illnesses. Knowledge of the disease pathway may help doctors and clinicians diagnose dengue at earlier stages. Researchers want to find out whether there are genetic factors that result in an increased or decreased risk of infection for individuals. Some people may be genetically susceptible to develop more severe symptoms than other people.

Scientists are also studying the dengue viruses to understand which factors are responsible for transmitting the virus to humans. Researchers are investigating how the dengue virus replicates itself and the structure of the viral components, such as the capsid, membrane, and envelope proteins. Scientists also want to know — how do the dengue viruses manage to avoid detection by the immune system? Because viruses can evolve and gain mutations over time, researchers are examining dengue viral genetics and evolution to investigate changes in viral genomes over time. These variations may help the virus hide from the immune system. Scientists know that particular viral sequences are associated with more severe dengue symptoms. In addition, certain dengue sequence variations may produce more deadly viruses with a greater potential for causing epidemics. This kind of information can help scientists monitor the regional spread of particularly dangerous dengue strains to help communities prevent or prepare for dengue outbreaks.

Other dengue research focuses on vector biology. What is vector biology? This field of dengue research studies the disease vector, Aedes mosquitoes. Vector biology studies mosquito ecology, population biology, genetics, and behaviors to understand how mosquitoes transmit the dengue viruses. Researchers can also study dengue transmission patterns. As one example, researchers studied dengue infections in children living in Nicaragua and saw that patterns of dengue transmission depended on changes in climate and changes in the dengue serotypes in the area. Large-scale studies of patterns in dengue transmission can provide essential information to resist the disease, identify and diagnose dengue cases, and implement mosquito-control efforts.

Diagnostics

Patients with severe dengue illnesses can be treated successfully if they are diagnosed as early as possible. Scientists are working on improving dengue diagnostics so that patients infected with dengue can be treated quickly. What would the ideal diagnostic test for dengue do? The ideal diagnostic test would be able to distinguish dengue from other diseases with similar symptoms and distinguish one dengue serotype from another. An ideal diagnostic test would be highly sensitive during the acute stage of the infection, quick and easy to use, and affordable.

How is dengue diagnosed? A number of laboratory methods are used to diagnose dengue, including detection of the dengue virus, viral RNA, viral antigens, and antibodies against the virus in the patient's blood or tissues (Figure 1). The virus can be detected in the blood for only four to five days after the onset of symptoms. During this early stage of the disease, isolation of the virus, viral RNA, and viral protein can be used to diagnose dengue.

The detection of antibodies (IgM and IgG) in the blood of an infected individual is an indirect method to diagnose dengue. This method is commonly used to diagnose dengue in the later stage of the disease, after the viral levels have decreased. Antibodies against dengue can be detected in most patients five days after the onset of symptoms, and IgG can be detected for many months and even years after an infection (Figure 2). During a primary (first) dengue infection, IgM levels are very high, but during a secondary infection, IgM levels are lower. The levels of IgG actually increase during a secondary infection. Therefore, clinicians can measure the amounts of IgM and IgG to decide whether a patient has a primary or a secondary dengue infection. This test can be useful because patients with secondary infections are more likely to have severe dengue than those who have not had a previous infection. Because dengue can be mistaken for other diseases such as yellow fever, measles, and influenza, it is best to confirm a diagnosis of dengue by detecting the antibody response and testing for direct evidence of the virus.

Have researchers developed any new diagnostic tests to diagnose dengue? Recently, scientists developed a rapid, one-step test to detect and distinguish all four dengue serotypes. This test is based on reverse transcription polymerase chain reaction amplification of the viral RNA, and it is a sensitive, rapid, and cost-effective tool to diagnose patients with dengue. A second approach involves diagnosing dengue infections by detecting NS1, one of the seven nonstructural dengue proteins. NS1 is produced in large quantities during dengue viral replication, and it can be detected as early as the first day the patient experiences a fever.

Is there a way to know which patients might develop severe dengue? Scientists want to find ways to quickly identify patients who are the most likely to develop severe dengue illnesses. To identify these patients, researchers must first discover predictive factors for severe dengue. One way researchers can discover these factors is to monitor the progression of the disease and look for factors that predict severe illness by taking frequent blood samples and ultrasound images from patients with dengue. Ultrasound can measure indicators of severe dengue, including the thickening of the gall bladder wall and excess fluids around the tissues and organs in the abdomen and chest cavity. Knowledge of additional predictive factors could help researchers design more effective diagnostic tests. Another strategy involves applying decision-making computer models to diagnose patients with dengue and predict their prognoses by using clinical data, such as the patient's platelet count and the presence of preexisting IgG antibodies against dengue in the blood.

Dengue Surveillance

What can other fields of research do to prevent and control dengue? In addition to performing basic research and improving diagnostics, improving dengue surveillance is an essential way to prevent and control dengue transmission. The World Health Organization — in partnership with ministries of health, research centers, and laboratories around the world — has developed a dengue surveillance system called DengueNet, a database that can be continuously updated to share current and historical data on dengue cases. The goals of DengueNet are to standardize reporting of dengue cases and to improve the preparedness of public health officials by providing early warnings prior to epidemics, which can help reduce fatality rates.

Monitoring mosquito populations is a first line of defense against dengue. Vector surveillance allows for a prompt response to control mosquito populations and limit dengue transmission. Studying vector competence, the ability of Aedes mosquitoes to acquire and transmit the dengue virus, can provide important information about variations in the transmission of the different dengue serotypes. Researchers have shown that delayed mosquito-control responses can lead to an exponential increase in both the number of infected people and health costs. Public health officials can prevent large dengue outbreaks by using surveillance information to plan mosquito-control efforts and interventions and to provide resources to affected areas. Vector surveillance is crucial for public health officials so that they can provide a prompt and preventative response to dengue.

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DENGUE VIRUS VIRULENCE AND DISEASES SEVERITY

• PMID: 26506730

The dengue virus is the causative agent of a wide spectrum of clinical manifestations, ranging from mild acute febrile illness to classical dengue fever, dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS). DHF and DSS are the potentially fatal forms of dengue virus infection, which has become an intractable public health problem in many countries. The pathogeneses of DHF/ DSS are not clearly understood. One hypothesis concerning virus virulence and the immune enhancement hypothesis has been debated. Although dengue disease severity has been associated with evidence of genetic differences in dengue strains, virus virulence has been difficult to measure because of the lack of in vivo and in vitro models of the disease.

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