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DENGUE, DENGUE HAEMORRHAGIC FEVER,DENGUE SHOCK SYNDROME
P Amin*, Sweety Bhandare**, Ajay Srivastava***
*Consultant BHIMS, **Resident, Cook Country Hosp. Chicago. ***Resident, Bombay Hospital, Mumbai.
INTRODUCTION
Dengue is an acute mosquito-transmitted viral disease characterized by fever, headache, muscle and joint pain, rash, nausea and vomiting. Some infections result in dengue haemorrhagic fever (DHF), a syndrome that in its most severe form can threaten the patient’s life, primarily through increased vascular permeability and shock. The case fatality in patients with dengue shock syndrome can be as high as 44%.[1]
EPIDEMIOLOGY
Epidemics of an illness compatible with DF (dengue fever) were first reported in medical literature in 1779 in Batavia (present-day Jakarta) and in 1780 in Philadelphia. Since then, epidemics have been reported in Calcutta (1824, 1853, 1871 and 1905), the West Indies (1827), Hong Kong (1901), Greece (1927-1928), Australia (1925-1926, 1942), the United States (1922), and Japan (1942-1945).2
Dengue is predominant in tropical areas mostly in South-east Asia, Africa and Southern parts of the US (Fig. 1). The first large epidemic of DHF (dengue haemorrhagic fever) occurred in Cuba in 1981 with 24,000 cases of DHF and 10,000 cases of DSS (dengue shock syndrome). In 1986 and 1987 massive outbreaks of dengue were reported in Brazil. In 1988, an epidemic of DF was reported at 1700m above sea level in Guerrero State, Mexico3 and in 1990 almost one-fourth of 3,00,000 people living in lquitos, Peru contracted DF.4
Fig 1
TRANSMISSION
The known natural hosts for dengue viruses are man, lower primates, and mosquitoes. The arthropod vectors are members of the genus Aedes that thrive both in urban and rural areas. [5-7] The predominant species implicated in disease transmission are A. aegypti and A. albopictus. [8-10]
Aedes aegypti, considered the most effective vector, originated in the forests of Africa and is found in Between 30 degrees north and 20 degrees south latitude.[11-14] The female mosquito feeds during the daytime, with peak activity in the mornings and late afternoons.[15,16] After feeding on a viraemic individual, the mosquito may transmit the virus directly by change of host, or after 8 to 10 days during the time the virus multiplies in the salivary glands.[17] The infected mosquito then remains capable of transmission for its entire life.[15] Transovarian transmission of dengue viruses has been documented.[18,19] and A. aegypti eggs are highly resistant to desiccation and can survive for extended periods.[20]
Aedes albopictus is indigenous to Southeast Asia, feeds during the day, and has been shown to have a higher biting frequency than A. aegypti.[21] Recently, it has been introduced into Nigeria, Europe, and the United States, apparently by shipments of used automobile tires. In the US Aedes albopictus has spread as far north as Chicago.[22-24] With the spread of adaptable cold-resistant strains, the chances for a major outbreak in Europe have increased.
THE VIRUS
Dengue viruses are members of the family Flaviviridae, which include the Japanese encephalitis virus and the yellow fever virus.[25] Four dengue virus serotypes [1,2,3] and [4] and various biotypes can be differentiated. The four serotypes are closely related antigenically.
Infection with one serotype provides life-long immunity to that virus but not to the others.
Mature Dengue virus consists of a single stranded ribonucleic acid genome (ssRNA), which has a positive polarity. The genome is surrounded by an icosahedral nucleocapsid with a diameter of 30 nm. The nucleocapsid is covered by a lipid envelope of 10 nm thickness derived from host cell membranes and contains the envelope and membrane proteins.[25]
The viral genome is 11kb. The 5’end of the RNA has a type I cap structure but lacks a poly A tail at the 3’ end.[26-28] It contains a single open reading frame of about 10,000 nucleotides encoding three structural and seven nonstructural proteins. The proteins are synthesized as a polyprotein of about 3000 amino acids that is processed cotranslationally and posttranslationally by viral and host proteases.[29,38]
The structural proteins include a capsid protein rich in arginine and lysine residues and a nonglycosylated prM protein. The major structural envelope protein is involved in the main biologic functions of the virus particle such as cell tropism, acid catalyzed membrane fusion and the induction of haemagglutination-inhibiting, neutralizing, and protective antibodies.
The non-structural proteins are addressed as NS1-7.
NS1, a glycoprotein is detected in high titers in patients with secondary dengue infections but its function is unknown.[39]
NS2 region, codes for two proteins (NS2A and NS2B), which are thought to be implicated in polyprotein processing.
NS3 is the viral proteinase that functions that functions in the cytosol.[40]
NS4 region codes for two small hydrophobic proteins that seem to be involved in the establishment of the membrane bound RNA replication complex.
NS5 codes for a protein with a molecular weight of 105,000 and is the most conserved flavivirus protein. This protein is believed to be the virus encoded RNA dependent RNA polymerase.[41]
NS6 and NS7 function yet to be found.
CLINICAL FEATURES
The clinical features of dengue virus infection vary from an asymptomatic infection to a febrile flu like infection (DF-dengue fever) to more severe form like DHF (dengue haemorrhagic fever), which can lead to DSS (dengue shock syndrome).[42,43] The clinical variability is poorly understood and seems to be related to the age, sex and the immunologic and nutritional status of the patient. DHF is most likely to develop in immune-competent, well-nourished girls between the ages of 7 and 12 years.[44] DHF is most common in children between ages 5 and 15 years.
DENGUE FEVER (DF)
The incubation period of dengue fever after the mosquito bite is usually 4 to 7 day (range is 3-14 days). DF may manifest with fever and a discrete macular or maculopapular rash. In this situation the clinical differentiation from other viral ill nesses may not be possible, recovery is rapid and the need for supportive treatment is minimal.[45]
The fever in severe cases can rise up to 39 degrees Celsius or higher. It persists for 5 to 6 days. Fever is characteristically biphasic and returns to almost normal in the middle of the febrile period giving rise to the saddleback temperature chart. It reaches its highest level during the last 24 hours before abatement. Symptoms include headache, usually frontal, and retroorbital pain, particularly when pressure is applied to the eyes. ("Fire is coming out of my eyes"). Arthralgias, myalgias and a maculopapular rash may appear at the onset. Some patients report severe backache (back-break fever), sore throat, or abdominal pain, which can be severe enough to be confused with appendicitis. The febrile period usually lasts up to 6 days during which time the rash may become diffusely erythematous with clear areas scattered in between, the so-called "islands of white in sea of red" (Fig. 2). These patients are lethargic with accompanying anorexia and nausea. Hepatomegaly can be present although splenomegaly is uncommon. Patients can have nausea and vomiting. Thrombocytopenia is characteristic with and serum hepatic enzymes may be elevated.
Fig 2
DENGUE HEMORRHAGIC FEVER (DHF)
The incubation period of DHF is unknown but is probably similar to that of DF. DHF commences acutely with high fever and many of the symptoms of DF. However, drowsiness and lethargy are more marked. There is increased vascular permeability, and abnormal haemostasis that can lead to hypovolaemia and hypotension and in severe cases, result in hypovolaemic shock, complicated by severe internal bleeding. The haemorrhagic manifestations appear usually by 3rd day and consist of scattered petechiae over the trunk, limbs and axillae. The petechiae are associated with a positive tourniquet test result. Bleeding at venepuncture sites is the rule and there may be haemorrhage from GI tract, nose and gums. After 2-7 days as fever begins to subside, signs of circulatory insufficiency can appear and pt is restless and sweaty, with cold extremities.
Transudate leaking due to excessive capillary permeability causes pleural effusion characteristically on the right side and abdominal ascites may be noted. In addition to the plasma leakage, DIC is present. With appropriate treatment, this phase usually lasts [24-48] hours.[46-47] Neurologic manifestations indicate infectious encephalitis and the virus is isolated in the CSF and brain tissue. Laboratory investigations in DHF reveal thrombocytopenia that may reach levels of 20,000 platelets/cubic mm. Haemoconcentration with haematocrit rise of 20% or more, hypoalbuminaemia, hypovolaemia and moderately elevated serum aminotransferases and blood urea nitrogen levels were documented. Partial thromboplastin time and thrombin time may be prolonged.[47] Hypofibrinogenaemia and complement depletion correlate with severity of the disease (Fig. 3).
Fig 3
DENGUE SHOCK SYNDROME (DSS)
DSS is defined as DHF with signs of circulatory failure, including narrow pulse pressure (â 20 mm Hg), or frank shock. The liver may be palpable and tender; and the liver enzymes are mildly elevated but jaundice is rare.[48,49] The four warning signs for impending shock are intense, sustained abdominal pain, persistent vomiting, restlessness or lethargy, and a sudden change from fever to hypothermia with sweating and prostration. The development of any of these signs or suggestion of hypotension is indicative of hospital management to prevent shock. [50] The patient may recover rapidly after volume replacement but shock may recur during the period of excessive capillary permeability. The case fatality rate in DHF can be as low as 0.2% if detected early and treated. Once shock has set in, the fatality rate may be as high as 12% to 44%. [51,52]
PATHOGENESIS
DHF is almost always found in individuals who had a previous experience with at least one of the four serotypes of dengue virus. This leads to the hypothesis of heterotypic antibodies from a previous dengue infection promoting the viral replication within the mononuclear leucocytes-the phenomenon of antibody-dependent enhancement.[53] Furthermore, the immunologic processes aimed at eliminating dengue virus infected cells can result in release of histamine and substances with vasoactive and procoagulant properties, the release of interferon-gamma, and the activation of complement.[54,56]
DHF results from an infection by a more virulent biotype of the virus or even from unfavourable host factors such as concomitant bacterial infections. DHF is known to be more common in Southeast Asia compared to Africa and America. Black individuals are relatively resistant to DHF/DSS due to a speculated "resistant gene".
The cause of bleeding in DHF appears to be due to thrombocytopenia, platelet dysfunction, disseminated intravascular coagulation and microvascular injury.
DIAGNOSIS
The clinical criteria for diagnosis are as follows: (1) fever; (2) haemorrhagic manifestations, including at least a positive tourniquet test result and a major or minor bleeding phenomenon; (3) hepatic enlargement; (4) shock (high pulse rate and narrowing of the pulse pressure to 20 mmHg or less, or hypotension). The laboratory criteria include (5) thrombocytopenia (â 100,000/mm3), and (6) haemoconcentration (haematocrit increase ô 20%). Thrombocytopenia with concurrent high haematocrit levels differentiates DHF from classic DF.
Currently routine laboratory diagnosis of dengue infections depends on virus isolation or the detection of dengue virus-specific antibodies. The isolation of viruses from clinical specimens can be carried out in cultured mosquito cells, such as AP-61 or C6/36 cells cultures.[57-60] When dengue virus serotype-specific monoclonal antibodies are used, virus identification by indirect immunofluorescence can be achieved within 2 weeks.[61,62] The development of mosquito inoculation techniques has not only improved the sensitivity but also reduced the time required for virus isolation and identification. Parenteral inoculation of adult. A. albopictus yields results in 7 days.[63,64] Virus isolation by intracerebral inoculation of Toxorhychitis splendens mosquito or its fourth instar larvae can even be achieved within 2 to 5 days. [65,66]
The serologic identification of the various types of dengue virus infection is complicated by the occurrence of cross-reactive antibodies to antigenic determinants shared by all four dengue viruses and other members of the flavivirus family. [67] The commonly used serologic test is the haemagglutination inhibition test. [68] In a primary infection dengue haemagglutination inhibition antibody titer is generally less than 1:20 in a sample collected within the first 4 days after the onset of symptoms. In the convalescent phase sample (collected 1 to 4 weeks after the onset of symptoms) a fourfold or greater rise in antibody titer is detected, with antibody titer â 1:1280. [69]
A secondary dengue infection is characterized by the rapid appearance of broadly cross-reactive antibodies. Haemagglutination inhibition titers of 1:20 in the acute-phase sample rise to ô to 1:2560 in the convalescent phase sample. An antibody titer of ô 1:1280 in the acute-phase sample without a fourfold or greater increase in the second sample also is considered presumptive of recent infection. An improved and less time-consuming method is a capture enzyme-linked immunosorbent assay that can detect specific anti-dengue IgM in a single acute-phase sample.[70]
Recently commercial kits for the detection of specific IgG as well as IgM antibodies have become available. They are based on a dot enzyme assay or a nitrocellulose membrane-based capture format, respectively, and should be suitable for field research.
An alternative to virus isolation is the detection of viral RNA by reverse transcription polymerase chain reaction. Reverse transcription polymerase chain reaction is a highly sensitive technique of particular value in the early diagnosis of dengue infection, but at present is only available in research settings.
TREATMENT
Patients with DF require rest, oral fluids to compensate for losses via diarrhoea or vomiting, analgesics, and antipyretics for high fever (acetaminophen) but not aspirin, so that platelet function will not be impaired. Steroids in DSS are not helpful.[74] With the earliest suspicion of threatened severe illness, an intravenous line should be placed so that fluids can be provided. Monitoring of blood pressure, haematocrit, platelet count, haemorrhagic manifestations, urinary output, and level of consciousness is important. Plasma leakage in DHF is very rapid and the haematocrit may continue to rise even while intravenous fluids are being administered; however, the "leaky capillary" period is short and intravenous fluids are usually required for only 1-2 days.[52,75-77] There is great variability from patient to patient, and the physician must adjust treatment using serial haematocrit, blood pressure, and urinary output data.[52,78] Insufficient volume replacement will allow worsening shock, acidosis, and disseminated intravascular coagulation, while fluid overload will produce massive effusions, respiratory compromise, and congestive heart failure. Because patients have loss of plasma (through increased vascular permeability into the serous spaces) they must be given isotonic solutions and plasma expanders, such as Ringer’s acetate or Ringer’s lactate, plasma protein fraction, and Dextran [40]. The recommended amount of total fluid replacement in 24 h is approximately the volume required for maintenance, plus replacement of 5% of bodyweight deficit, but this volume is not administered uniformly throughout the 24 h. A bolus of 10-20 ml of an isotonic solution per kg bodyweight is given in case of shock, and repeated every 30 min until circulation improves and urinary output is adequate. Vital signs should be measured every 30-60 min and haematocrit every 2-4 h, then less frequently as the patient’s condition stabilizes.[52, 75-77]
Placement of a central-venous-pressure line is hazardous in patients with haemorrhagic tendencies but may be necessary, especially when more than 60 ml/kg of fluids has been given without improvement. An expert in a special care area should insert the line. It is used to estimate filling pressures and to guide further intravenous fluid administration. An arterial line will help in the assessment of arterial blood gases, acidbase status, coagulation profiles, and electrolytes in the haemodynamically unstable patient, helping to identify early respiratory compromise.
Monitoring should be continued for at least a day after defervescence. Once the patient begins to recover, extravasated fluid is rapidly reabsorbed, causing a drop in haematocrit. Before discharge, the patient should meet the following criteria: absence of fever for 24 h (without antipyretics) and a return of appetite; improvement in the clinical picture; hospital care for at least 3 days after recovery from shock; no respiratory distress from pleural effusion or ascites; stable haematocrit; and platelet count greater than 50,000/ml76 Because convalescent-phase diagnostic samples are often difficult to obtain, a second blood sample should always be taken on the day of discharge.
PROSPECTS FOR CONTROL
Vaccine development
An effective vaccine will have to be tetravalent because pre-existing heterotypic dengue antibody is a risk factor for DHF. Candidate attenuated vaccine viruses have been evaluated in phase I and II trials in Thailand, and a tetravalent formulation is currently undergoing repeat phase I and II trials.[79] Advances have also been made with second generation recombinant dengue vaccines. A cDNA infectious clone of the DEN-2 PDK-53 vaccine candidate virus has been constructed, and work is in progress to construct chimeric viruses by inserting the capsid, premembrane, and envelope genes of DEN 1, 3 and 4 into the DEN-2 PDK-53 backbone. These recombinants, through genetic manipulation, may be made to replicate faster, be more immunogenic and safer.[80,81] However, an effective, safe and affordable vaccine is not an immediate prospect.[82]
Vector control
At present dengue transmission can only be reduced by mosquito control. The task might seem a simple matter of the treatment or elimination of infested containers. Source (container) reduction campaigns have been very successful but they are hard to sustain, mainly because they are labour intensive, require discipline and diligence, and are plagued by diminishing returns. Emphasis has shifted first to organochloride insecticides and later to organophosphorus larvicides, and aerosols targeted at adult mosquitoes and mostly applied outdoors as ultra-low volume (ULV) concentrates. The aerosols are principally recommended for emergency control during epidemic transmission as part of an integrated vector elimination effort, including environmental management, source reduction and larvicides.[76] Nevertheless, their routine use as the principal response even before and after dengue epidemics has become widespread. This is regrettable, because ULV aerosols have very limited surprisingly, therefore, there is no well-documented example of interruption of a dengue epidemic by outdoor ULV treatments.[76] Indoor treatments are probably much more effective but are very labour-intensive and intrusive.
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