Dengue fever, a very old disease, has reemerged in the past 20 years with an expanded geographic distribution of both the viruses and the mosquito vectors, increased epidemic activity, the development of hyperendemicity (the cocirculation of multiple serotypes), and the emergence of dengue hemorrhagic fever in new geographic regions. In 1998 this mosquito-borne disease is the most important tropical infectious disease after malaria, with an estimated 100 million cases of dengue fever, 500,000 cases of dengue hemorrhagic fever, and 25,000 deaths annually. The reasons for this resurgence and emergence of dengue hemorrhagic fever in the waning years of the 20th century are complex and not fully understood, but demographic, societal, and public health infrastructure changes in the past 30 years have contributed greatly. This paper reviews the changing epidemiology of dengue and dengue hemorrhagic fever by geographic region, the natural history and transmission cycles, clinical diagnosis of both dengue fever and dengue hemorrhagic fever, serologic and virologic laboratory diagnoses, pathogenesis, surveillance, prevention, and control. A major challenge for public health officials in all tropical areas of the world is to devleop and implement sustainable prevention and control programs that will reverse the trend of emergent dengue hemorrhagic fever.

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Dengue and Dengue Hemorrhagic Fever

BACKGROUND In 2007, physicians on Yap Island reported an outbreak of illness characterized by rash, conjunctivitis, and arthralgia. Although serum from some patients had IgM antibody against dengue virus, the illness seemed clinically distinct from previously detected dengue. Subsequent testing with the use of consensus primers detected Zika virus RNA in the serum of the patients but no dengue virus or other arboviral RNA. No previous outbreaks and only 14 cases of Zika virus disease have been previously documented. METHODS We obtained serum samples from patients and interviewed patients for information on clinical signs and symptoms. Zika virus disease was confirmed by a finding of Zika virus RNA or a specific neutralizing antibody response to Zika virus in the serum. Patients with IgM antibody against Zika virus who had a potentially cross-reactive neutralizing-antibody response were classified as having probable Zika virus disease. We conducted a household survey to estimate the proportion of Yap residents with IgM antibody against Zika virus and to identify possible mosquito vectors of Zika virus. RESULTS We identified 49 confirmed and 59 probable cases of Zika virus disease. The patients resided in 9 of the 10 municipalities on Yap. Rash, fever, arthralgia, and conjunctivitis were common symptoms. No hospitalizations, hemorrhagic manifestations, or deaths due to Zika virus were reported. We estimated that 73% (95% confidence interval, 68 to 77) of Yap residents 3 years of age or older had been recently infected with Zika virus. Aedes hensilli was the predominant mosquito species identified. CONCLUSIONS This outbreak of Zika virus illness in Micronesia represents transmission of Zika virus outside Africa and Asia. Although most patients had mild illness, clinicians and public health officials should be aware of the risk of further expansion of Zika virus transmission.

https://www.nejm.org/doi/pdf/10.1056/NEJMoa0805715

Zika virus outbreak on Yap Island, Federated States of Micronesia.

Dengue and dengue hemorrhagic fever.

Dengue fever and dengue haemorrhagic fever are important arthropod-borne viral diseases. Each year, there are ∼50 million dengue infections and ∼500,000 individuals are hospitalized with dengue haemorrhagic fever, mainly in Southeast Asia, the Pacific and the Americas. Illness is produced by any of the four dengue virus serotypes. A global strategy aimed at increasing the capacity for surveillance and outbreak response, changing behaviours and reducing the disease burden using integrated vector management in conjunction with early and accurate diagnosis has been advocated. Antiviral drugs and vaccines that are currently under development could also make an important contribution to dengue control in the future.

Dengue: a continuing global threat

Dengue viruses occur as four antigenically related but distinct serotypes transmitted to humans by Aedes aegypti mosquitoes. These viruses generally cause a benign syndrome, dengue fever, in the American and African tropics, and a severe syndrome, dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), in Southeast Asian children. This severe syndrome, which recently has also been identified in children infected with the virus in Puerto Rico, is characterized by increased vascular permeability and abnormal hemostasis. It occurs in infants less than 1 year of age born to dengue-immune mothers and in children 1 year and older who are immune to one serotype of dengue virus and are experiencing infection with a second serotype. Dengue viruses replicate in cells of mononuclear phagocyte lineage, and subneutralizing concentrations of dengue antibody enhance dengue virus infection in these cells. This antibody-dependent enhancement of infection regulates dengue disease in human beings, although disease severity may also be controlled genetically, possibly by permitting and restricting the growth of virus in monocytes. Monoclonal antibodies show heterogeneous distribution of antigenic epitopes on dengue viruses. These epitopes serve to regulate disease: when antibodies to shared antigens partially neutralize heterotypic virus, infection and disease are dampened; enhancing antibodies alone result in heightened disease response. Further knowledge of the structure of dengue genomes should permit rapid advances in understanding the pathogenetic mechanisms of dengue.

https://science.sciencemag.org/content/sci/239/4839/476.full.pdf

Pathogenesis of dengue: challenges to molecular biology

Dengue virus type 1 has been isolated in Aedes albopictus cell strain, from sera of patients living in the Nova Iguacu county, by Rio de Janeiro. The clinical picture was characterized by fever, headache, retrobulbar pain, backache, pains in the muscles and the joints and prostration. Studies in paired sera confirmed the presence of recent infection by dengue virus type 1. The outbreak reached adjacent areas, including Rio de Janeiro city (May, 1986).

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An outbreak of dengue virus at Rio de Janeiro - 1986

Immunohistochemical procedure (avidin biotin peroxidase complex) was applied in formalin-fixed and paraffin-embedded tissues obtained from 5 fatal cases of dengue infection associated with encephalopathy. Dengue virus antigen was demonstrated in the cytoplasm of phagocytic mononuclear cells from liver, spleen, and lung. Moreover, dengue viral antigens were here, to our knowledge, first demonstrated in the central nervous system (CNS) and numerous immunolabelled cells were found in brain sections from 3 cases. Extended immunohistochemical studies carried out in 1 case showed virus-positive cells mostly located within Virchow Robin space of medium size and small veins, infiltrating the white and grey matter, and often situated close to neurons displaying apparent cytopathic features. Furthermore, immunostaining for CD68 antigens demonstrated that most CD68+ macrophages and dengue antigen-positive cells share similar morphology and localization, suggesting a unique identity for at least part of these cells. Since in dengue fever, virus replicates mostly in cells of macrophage lineage, our results seem to indicate that infiltration of virus-infected macrophages could be one of the pathways by which viruses enter the brain in dengue encephalitis. Whether bone marrow-derived infected macrophages and viral-free particles induce CSN lesions through immune, metabolic, and/or direct viral-induced mechanisms will be essential to better understand the pathogenesis and provide new therapeutic strategies for dengue-associated encephalitis. As the evidence of tissue damage was nonspecific, the detection of virus antigen by immunoperoxidase technique appeared to be highly reliable for dengue diagnosis.

Retrospective study on dengue fatal cases

Evaluation of an IgG enzyme-linked immunosorbent assay for dengue diagnosis

Background 
Dengue is associated with explosive urban epidemics and has become a major public health problem in many tropical developing countries, including Brazil. The laboratory diagnosis of dengue can be carried out using several approaches, however sensitive and specific assays useful to diagnose in the early stage of fever are desirable. The flavivirus non-structural protein NS1, a highly conserved and secreted glycoprotein, is a candidate protein for rapid diagnosis of dengue in endemic countries.


Methodology/Principal Findings 
We aimed to evaluate the potential use of 3 commercial kits in a panel of 450 serum samples for early diagnosis of dengue in Brazil. The PanBio Early ELISA (PanBio Diagnostics) showed a sensitivity of 72.3% (159/220) and a specificity of 100%, while the sensitivity of the Platelia™ NS1 assay (Biorad Laboratories) was 83.6% (184/220). However, the highest sensitivity (89.6%; 197/220) was obtained by using the NS1 Ag Strip (Biorad Laboratories). A lower sensitivity was observed in DENV-3 cases by all 3 kits. Serum positive by virus isolation were more often positive than cases positive by RT-PCR by all three assays and a higher detection rate was observed during the first four days after the onset of the symptoms. The presence or absence of IgM showed no influence in the confirmation by the pan-E Early ELISA (P = 0,6159). However, a higher confirmation by both Platelia™ NS1 (Biorad) and Dengue NS1 Ag Strip (Biorad) in the absence of IgM was statistically significant (P<0,0001 and P = 0,0008, respectively). Only the Platelia™ NS1 test showed a higher sensitivity in confirming primary infections than secondary ones.


Conclusions/Significance 
The results indicate that commercial kits of dengue NS1 antigen are useful for the laboratory diagnosis of acute primary and secondary dengue. It can be used in combination with the MAC-ELISA for case detection and as screening test to complement viral isolation.

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Comparison of Three Commercially Available Dengue NS1 Antigen Capture Assays for Acute Diagnosis of Dengue in Brazil

During 1990 and 1991, dengue fever was detected in the State of Rio de Janeiro, Brazil. It occurred in two epidemic waves; one, from January to August 1990, caused predominantly by dengue virus type 1 (DEN-1) the other from October 1990 to May 1991 caused by type 2 virus (DEN-2). Dengue was confirmed by virus isolation and/or IgM capture enzyme-linked immunosorbent assay (MAC-ELISA) in 2109/5964 (35.4%) of the cases. DEN-2 virus was isolated from 180 patients. HAI tests indicated that of these previous infection with DEN-1 had occurred in 130 (72%). The epidemic was classified as dengue fever, but severe and even fatal cases occurred in association with secondary infection.

Hermann G. Schatzmayr

Papers

An outbreak of dengue virus at Rio de Janeiro - 1986

Retrospective study on dengue fatal cases

Evaluation of an IgG enzyme-linked immunosorbent assay for dengue diagnosis

Comparison of Three Commercially Available Dengue NS1 Antigen Capture Assays for Acute Diagnosis of Dengue in Brazil

Dengue epidemic in the stage of Rio de Janeiro, Brazil, 1990-1: co-circulation of dengue 1 and dengue 2 serotypes.