A model of dengue fever

Background  

Dengue is a disease which is now endemic in more than 100 countries of Africa, America, Asia and the Western Pacific. It is transmitted to the man by mosquitoes (Aedes) and exists in two forms: Dengue Fever and Dengue Haemorrhagic Fever. The disease can be contracted by one of the four different viruses. Moreover, immunity is acquired only to the serotype contracted and a contact with a second serotype becomes more dangerous.     

Role of cognitive parameters in dengue hemorrhagic fever and dengue shock syndrome

Dengue is becoming recognized as one of the most important vector-borne human diseases. It is predominant in tropical and subtropical zones but its geographical distribution is progressively expanding, making it an escalating global health problem of today. Dengue presents with spectrum of clinical manifestations, ranging from asymptomatic, undifferentiated mild fever, dengue fever (DF), to dengue hemorrhagic fever (DHF) with or without shock (DSS), a life-threatening illness characterized by plasma leakage due to increased vascular permeability. Currently, there are no antiviral modalities or vaccines available to treat and prevent dengue. Supportive care with close monitoring is the standard clinical practice. The mechanisms leading to DHF/DSS remains poorly understood. Multiple factors have been attributed to the pathological mechanism, but only a couple of these hypotheses are popular in scientific circles. The current discussion focuses on underappreciated factors, temperature, natural IgM, and endotoxin, which may be critical components playing roles in dengue pathogenesis.     

Hemophagocytic syndrome associated with dengue hemorrhagic fever

The haemophagocytic syndrome is characterised by systemic proliferation of non-neoplastic histiocytes showing haemophagocytosis resulting in blood cytopenia. It has been described in relation to several viruses earlier. We present three patients with haemophagocytic syndrome (HFS) secondary to dengue haemorrhagic fever (DHF) confirmed by standard laboratory tests. The patients were hospitalized at the University Hospital (Hospital Universitario Ramón González Valencia-HURGV) in Bucaramanga, Colombia, during the past two years. They were all school-aged patients who presented DHF with intense abdominal pain, prolonged fever, hypotension and painful hepatomegaly. Laboratory tests showed thrombocytopenia, anaemia and leukopenia. A calculous cholecystitis was observed in the abdominal ultrasonography, and all bone marrow aspirations showed that platelets, red and white blood cells were phagocyted by histiocytes. According to the International Society of Histiocytosis, SHF is defined and classified in three major categories; the reported cases corresponded to histiocytosis class II, specifically to secondary SHF. Diverse associations of this syndrome correspond to viral infections and some other non-infectious diseases. A difference has been established between primary SHF and secondary SHF. Finally, we emphasize that these three patients had an atypical evolution of FHD, being prolonged fever and persistent abdominal pain the most important symptoms. The authors recommend that a bone marrow aspiration should be carried out as part of the differential diagnosis study in prolonged fever associated with dengue, as there is a possibility that this complication could be secondary SHF.     

Nitric oxide in dengue and dengue haemorrhagic fever: necessity or nuisance?

Advances in free radical research show that reactive oxygen and nitrogen oxide species, for example superoxide, nitric oxide (NO) and peroxynitrite, play an important role in the pathogenesis of different viral infections, including dengue virus. The pathogenic mechanism of dengue haemorrhagic fever (DHF) is complicated and is not clearly understood. The hallmarks of the dengue disease, the antibody-dependent enhancement, the shift from T-helper type 1 (Th1) to Th2 cytokine response and the cytokine tsunami resulting in vascular leakage can now be explained much better with the knowledge gained about NO and peroxynitrite. This paper makes an effort to present a synthesis of the current opinions to explain the pathogenesis of DHF/shock syndrome with NO on centre stage.     

Implications of previous subclinical dengue infection but not virus load in dengue hemorrhagic fever

In a study comparing the virus load and immune reaction between patients with primary and secondary dengue-2 (DEN-2) infections in a hospital-based analysis, we found that 40.7% (55/135) of the 135 patients had secondary DEN-2 infection following a DEN-2 outbreak in southern Taiwan. Most of the secondary infections had subclinical primary dengue infections (78.2%; 43/55). Patients with secondary DEN-2 infections had lower platelet counts, and blood interferon-alpha and virus load, but significantly higher interleukin-10 (P=0.030) and anti-DEN-1 neutralization titers (P=0.013) than those with primary infection. Patients with secondary DEN-2 infection also had a higher rate of dengue hemorrhagic fever (DHF) (61.7% vs. 36.3%). A previous subclinical dengue infection is involved in the secondary DEN-2 infection associated with altered immune reaction and higher DHF rate, but lower blood virus load.     

Tackling dengue fever: Current status and challenges

According to recent statistics, 96 million apparent dengue infections were estimated worldwide in 2010. This figure is by far greater than the WHO prediction which indicates the rapid spread of this disease posing a growing threat to the economy and a major challenge to clinicians and health care services across the globe particularly in the affected areas.This article aims at bringing to light the current epidemiological and clinical status of the dengue fever. The relationship between genetic mutations, single nucleotide polymorphism (SNP) and the pathophysiology of disease progression will be put into perspective. It will also highlight the recent advances in dengue vaccine development.Thus far, a significant progress has been made in unraveling the risk factors and understanding the molecular pathogenesis associated with the disease. However, further insights in molecular features of the disease and the development of animal models will enormously help improving the therapeutic interventions and potentially contribute to finding new preventive measures for population at risk.     

Scientists try new strategy to eradicate dengue fever

In a bid to reduce the risk of dengue fever in parts of Vietnam, the Australian Foundation for the Peoples of Asia and the Pacific, an aid organization, recently completed a 3-year program using the mesocyclops crustacean, an organism about 1 mm long which eats the larvae of mosquitos which transmit dengue fever. The program appears to eradicated the larvae from the northern Vietnamese province of Phan Boi, and there was a 75% success rate in other provinces. The Queensland Institute of Medical Research and the Vietnam National Institute of Hygiene and Epidemiology were the organizations involved in coordinating drops of the organism into mosquito breeding areas such as wells, water tanks, and household water containers. A community education and clean-up program was also implemented to teach residents about the importance of throwing away unused buckets and other containers which could hold stagnant water and become potential breeding grounds for disease. It is important to prevent dengue because existing treatments are inadequate.     

Dengue and dengue haemorrhagic fever: Indian perspective

The relationship of this country with dengue has been long and intense. The first recorded epidemic of clinically dengue-like illness occurred at Madras in 1780 and the dengue virus was isolated for the first time almost simultaneously in Japan and Calcutta in 1943–1944. After the first virologically proved epidemic of dengue fever along the East Coast of India in 1963–1964, it spread to allover the country. The first full-blown epidemic of the severe form of the illness, the dengue haemorrhagic fever/dengue shock syndrome occurred in North India in 1996. Aedes aegypti is the vector for transmission of the disease. Vaccines or antiviral drugs are not available for dengue viruses; the only effective way to prevent epidemic degure fever/dengue haemorrhagic fever (DF/DHF) is to control the mosquito vector, Aedes aegypti and prevent its bite. This country has few virus laboratories and some of them have done excellent work in the area of molecular epidemiology, immunopathology and vaccine development. Selected work done in this country on the problems of dengue is presented here.     

Progress towards understanding the pathogenesis of dengue hemorrhagic fever

Dengue virus (DENV) is a mosquito-borne virus belonging to the Flaviviridae family. There are 4 serotypes of DENV that cause human disease through transmission by mosquito vectors. DENV infection results in a broad spectrum of clinical symptoms, ranging from mild fever to dengue hemorrhagic fever (DHF), the latter of which can progress to dengue shock syndrome (DSS) and death. Researchers have made unremitting efforts over the last half-century to understand DHF pathogenesis. DHF is probably caused by multiple factors, such as virus-specific antibodies, viral antigens and host immune responses. This review summarizes the current progress of studies on DHF pathogenesis, which may provide important information for achieving effective control of dengue in the future.

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Knowledge, awareness and practices regarding dengue fever among the adult population of dengue hit cosmopolitan

Background

The World health Organization (WHO) declares dengue and dengue hemorrhagic fever to be endemic in South Asia. Despite the magnitude of problem, no documented evidence exists in Pakistan which reveals the awareness and practices of the country''s adult population regarding dengue fever, its spread, symptoms, treatment and prevention. This study was conducted to assess the level of knowledge, attitudes and practices regarding dengue fever in people visiting tertiary care hospitals in Karachi, Pakistan.

Methods

A cross-sectional pilot study was conducted among people visiting tertiary care hospitals in Karachi. Through convenience sampling, a pre-tested and structured questionnaire was administered through a face-to-face unprompted interview with 447 visitors. Knowledge was recorded on a scale of 1–3.

Results

About 89.9% of individuals interviewed had heard of dengue fever. Sufficient knowledge about dengue was found to be in 38.5% of the sample, with 66% of these in Aga Khan University Hospital and 33% in Civil Hospital Karachi. Literate individuals were relatively more well-informed about dengue fever as compared to the illiterate people (p<0.001). Knowledge based upon preventive measures was found to be predominantly focused towards prevention of mosquito bites (78.3%) rather than eradication of mosquito population (17.3%). Use of anti- mosquito spray was the most prevalent (48.1%) preventive measure. Television was considered as the most important and useful source of information on the disease.

Conclusion

Adult population of Karachi has adequate knowledge related to the disease ‘dengue’ on isolated aspects, but the overall prevalence of ‘sufficient knowledge’ based on our criteria is poor. We demonstrated adequate prevalence of preventive practices against the disease. Further studies correlating the association between knowledge and its effectiveness against dengue will be helpful in demonstrating the implications of awareness campaigns.     

A case of dengue hemorrhagic fever in a Japanese child

A 6-year-old Japanese girl contracted a febrile illness with hemorrhagic manifestations when she traveled in Indonesia. A remarkable decrease in the numbers of platelets and white blood cells was observed in her acute-phase blood specimens. Her father, who accompanied her, showed dengue fever-like symptoms at almost the same time as her illness. It was determined by serological tests that they were infected with dengue virus type 1. Moreover, she showed a secondary antibody response to the flavivirus due to the pre-existing antibody to Japanese encephalitis virus. This is the first confirmed case of dengue hemorrhagic fever (DHF) in Japanese people.     

Dengue and dengue haemorrhagic fever: implications of host genetics

Little is known of the role of human leucocyte antigen (HLA) alleles or non-HLA alleles in determining resistance, susceptibility or the severity of acute viral infections. Dengue fever (DF) and dengue haemorrhagic fever (DHF) are suitable models for immunogenetic studies, yet only superficial efforts have been made to study dengue disease to date. DF and DHF can be caused by both primary and secondary infection by any of the four serotypes of the dengue virus. Differences in host susceptibility to infectious disease and disease severity cannot be attributed solely to the virus virulence. Variations in immune response, often associated with polymorphism in the human genome, can now be detected. Data on the influence of human genes in DF and DHF are discussed here in relation to (1) associations between HLA polymorphism and dengue disease susceptibility or resistance, (2) protective alleles influencing progression to severe disease, (3) alleles restricting CD4(+) and CD8(+) T lymphocytes, and (4) non-HLA genetic factors that may contribute to DHF evolution. Recent discoveries regarding genetic associations in other viral infections may provide clues to understanding the development of end-stage complications in dengue disease. The scanty positive data presented here indicate a need for detailed genetic studies in different ethnic groups in different countries during the acute phase of DF and DHF on a larger number of patients.     

Role of interleukin-12 in patients with dengue hemorrhagic fever

Interleukin (IL)-12 has a broad range of activities including regulation of cytokine synthesis and selective promotion of Th1-type cell development. A shift from a Th1-type response to Th2-type has been suggested to be important in the pathogenesis of dengue hemorrhagic fever (DHF). This study was undertaken to investigate the possible role of IL-12 in this shift. A total of 76 patients with various grades of dengue illness and 21 normal healthy controls were tested for IL-12 levels in serum samples and IL-12 mRNA in their peripheral blood mononuclear cells. The results showed that the levels of IL-12 were the highest in patients with dengue fever (270+/-102 pg ml(-1)) followed by decreasing levels in the patients with DHF grade I (198+/-86 pg ml(-1); P<0.05) and DHF grade II (84+/-52 pg ml(-1); P<0.001). Neither IL-12 nor its mRNA could be detected in the patients with DHF grades III and IV. The cytokine appeared and reached peak levels during the first 4 days of illness, started to decline by day 5-8 and disappeared by day 9 onwards. The absence of IL-12 during severe illness and late phases of the disease may be responsible for the shift to a Th2-type response and thus for the pathogenesis of DHF.     

Chimeric yellow fever/dengue virus as a candidate dengue vaccine: quantitation of the dengue virus-specific CD8 T-cell response

We have constructed a chimeric yellow fever/dengue (YF/DEN) virus, which expresses the premembrane (prM) and envelope (E) genes from DEN type 2 (DEN-2) virus in a YF virus (YFV-17D) genetic background. Immunization of BALB/c mice with this chimeric virus induced a CD8 T-cell response specific for the DEN-2 virus prM and E proteins. This response protected YF/DEN virus-immunized mice against lethal dengue encephalitis. Control mice immunized with the parental YFV-17D were not protected against DEN-2 virus challenge, indicating that protection was mediated by the DEN-2 virus prM- and E-specific immune responses. YF/DEN vaccine-primed CD8 T cells expanded and were efficiently recruited into the central nervous systems of DEN-2 virus challenged mice. At 5 days after challenge, 3 to 4% of CD8 T cells in the spleen were specific for the prM and E proteins, and 34% of CD8 T cells in the central nervous system recognized these proteins. Depletion of either CD4 or CD8 T cells, or both, strongly reduced the protective efficacy of the YF/DEN virus, stressing the key role of the antiviral T-cell response.     

Alternate hypothesis on the pathogenesis of dengue hemorrhagic fever (DHF)/dengue shock syndrome (DSS) in dengue virus infection

Dengue fever, caused by infection with dengue virus, is not a new disease, but recently because of its serious emerging health threats, coupled with possible dire consequences including death, it has aroused considerable medical and public health concerns worldwide. Today, dengue is considered one of the most important arthropod-borne viral diseases in humans in terms of morbidity and mortality. Globally, it is estimated that approximate 50 to 100 million new dengue virus infections occur annually. Among these, there are 200,000 to 500,000 cases of potential life-threatening dengue hemorrhagic fever (DHF)/dengue shock syndrome (DSS), characterized by thrombocytopenia and increased vascular permeability. The death rate associated with the more severe form DHF/DSS is approximately 5%, predominantly in children under the age of 15. Although intensive efforts have been made to study the early clinical pathophysiology of dengue infection with the objective to identify the potential cause of DHF, results or data that have accumulated from different regions of the world involving studies of different ethnicity groups are inconsistent at present in terms of identifying a unified hypothesis for the pathogenesis of DHF/DSS. Thus, the potential mechanisms involved in the pathogenesis of DHF and DSS remain elusive. The purpose of this review is to identify alternate factors, such as innate immune parameters, hyper-thermal factors, conditioning of neutralizing antibody, concept of vector transmission, and physical status of virus in viremic patients that may play a role in the induction of DHF and DSS, which might have directly or indirectly contributed to the discrepancies that are noted in the literature reported to date. It is the hope that identification of an alternative explanation for the pathogenesis of DHF/DSS will pave the way for the institution of new strategies for the prevention of this complicated disease.