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Dengue fever is an acute febrile infectious disease, caused by all four serotypes (1, 2, 3 or 4) of a virus from genus Flavivirus, called dengue virus. It’s the most prevalent flavivirus infection of humans, with a worldwide distribution in the tropics and warm areas of the temperate zone corresponding to that of the principal vector, Aedes aegypti. When simultaneous or sequential introduction of two or more serotypes occurs in the same area, there may be an increased number of cases with worse clinical presentation (dengue hemorrhagic fever). The term ‘hemorrhagic’ is imprecise, because what characterizes this form of the disease is not the presence of hemorrhagic manifestations, but the abrupt increase of capillary permeability, with diffuse capillary leakage of plasma, hemoconcentration and, in some cases, with non-hemorrhagic hypovolemic shock (dengue shock syndrome).
The highest incidence of dengue is in southeast Asia, India and the American tropics, where A. aegypti can be found. In the 1980s, dengue emerged in explosive epidemics in Rio de Janeiro (1986 - serotype 1 and 1990 - serotype 2 was isolated in Niterói city), São Paulo and in many other towns and cities in Brazil. In areas such as southeast of Asia, where all four dengue virus types are hyperendemic, children are almost exclusively affected, and seroprevalence approaches 100% by young adulthood.
Transmission occurs by the bite of Aedes aegypti female mosquitoes - the same vector of urban yellow fever - a day-active species with low fly-autonomy that is abundant in and around human habitations. In Brazil and other countries Aedes albopictus may also be responsible for transmission. Viremic humans (till the fifth day of disease) serve as the source of virus for mosquito infection; there is not person-to-person transmission. Movement of viremic humans provides the principal means of spread, and rapid air travel is a factor in most recent epidemic emergences.
Although homotypic immunity is complete and lifelong, cross-protection between virus types is incomplete and transient. As mentioned before, there is a strict association between reinfection by another serotype and the occurrence of dengue hemorrhagic fever (DHF), due to immunopathologic processes, such as immune enhancement and immune clearance (see bibliography). Outbreaks usually occur in summer, when ambiental conditions are ideal for vectors’ proliferation.
Incubation period: 3 - 6 days; some cases may reach 15 days.
Dengue Fever:
Symptoms begin with the abrupt onset of high fever, severe malaise, headache, retro-orbital pain, myalgia (lumbosacral pain, also involving legs), frequently accompanied by sore throat, nausea, vomiting, epygastric pain and diarrhea. In children, sore throat and abdominal pain are predominant. Defervescence occurs between days 3 and 8, usually followed by minor hemorrhagic phenomena (petechiae, purpura, epistaxis) and the onset of a maculopapular or morbilliform, sometimes pruritic rash on the trunk , with a centrifugal spread involving limbs, face, palms and soles. Some cases may advance with severe gastrointestinal bleeding and shock. Thus, the presence of hemorrhagic manifestations is not exclusively for ‘dengue hemorrhagic fever’.
Dengue Hemorrhagic Fever (DHF):
The early phase of illness is indistinguishable from dengue fever. After 2 - 5 days, however (defervescence period), a few cases in the first infection, in contrast with a significant number of cases after reinfection by another serotype may present with thrombocytopenia (< 100.000 /mm3) and hemoconcetration, the first usually preceeding the second. Hemorrhagic manifestations may or may not occur; the spleen is not palpable, but hepatic enlargement and tenderness is a sign of bad prognosis. Other manifestations include pleural effusion and hypoalbuminemia, encephalopathy with normal cerebrospinal fluid.
Diffuse cappilary leakage of plasma is responsible for the hemoconcentration. In the presence of hemoconcentration and thrombocytopenia, the pacient is considered to be seized by dengue hemorrhagic fever and classified according to the following World Health Organization classification:
Grade I - thrombocytopenia + hemoconcentration. Absence of spontaneous bleeding.The case-fatality of DHF/DSS is 10% or higher if untreated. With supportive treatment, fewer than 1% of such cases succumb. Recovery is rapid and without sequelae.
Although the etiologic diagnosis of dengue is extremely important and desirable in terms of Health Public Care, it’s absolutely unnecessary for the early institution of supportive therapy. Dengue is always a diagnosis of exclusion, and other diseases with the same initial clinical presentation must be suspected (see below). In order to help the clinician in the detection of severe forms of dengue (DHF/DSS), even when the definitive diagnosis has not been made yet, there are three essential laboratory tests that may help in the evaluation of the real clinical conditions of the patient and its early supportive management: total white blood cells count, total platelets count and micro-hematocrit.
Laboratory Findings:
. Total White Blood Cells Count: In case of dengue, this test will reveal leukopenia. The presence of leukocytosis and neutrophilia excludes the possibility of dengue and bacterial infections (leptospirosis, meningoencephalitis, septicemy, pielonephritis etc.) must be considered.
. Thrombocytopenia (< 100.000 /mm3): Total platelets count must be obtained in every patient with symptoms suggestive of dengue for three or more days of presentation. Leptospirosis, measles, rubella, meningococcemia and septicemy may also course with thrombocytopenia.
. Hematocrit (micro-hematocrit): According to the definition of DHF, it’s necessary the presence of hemoconcentration (hematocrit elevated by > 20%); when it’s not possible to know the previous value of hematocrit, we must regard as significantly elevated the results > 45%.
Etiologic Confirmation:
It can be obtained by isolating infectious virus, demonstrating viral antigen by immunoassay, or viral genome by PCR in serum or blood.
Serologic diagnosis is achieved by IgM antibody-capture by enzyme-linked immunosorbent assay (MAC - ELISA) in two blood specimen taken in a period of 14 days from each other. The first specimen, taken till the seventh day of the disease, can also be useful for virus isolation by inoculation of A. albopictus cells or adults mosquitoes, with specific indentification of virus by immunofluorescence tests employing monoclonal antibody reagents.
Postmortem diagnosis is made by virus isolation or by demonstration of viral antigen (direct immunofluorescence) from two-specimen visceral fragments (liver, spleen, linfonodes, thymus).
. Leptospirosis - Increased erythrocyte sedimentation rate, total WBC elevated with neutrophilia, transaminases levels slightly elevated and increased BUN and serum creatinine. The presence of jaundice (indicative of severe forms of leptospirosis) + epidemiologic data pratically exclude the diagnosis of dengue.
. Respiratory Infections - ‘Common cold’ is seldom mistaken with dengue due to the absence of fever. In relation to the ‘Influenza-like syndromes’, differential diagnosis is made by the presence of respiratory symptoms (cough, sore throat, nasal discharge), with higher incidence in the winter; Bacterial pneumonias usually present with chest pain (pleurodynia), produtive cough and total WBC elevated with neutrophilia. Diagnosis can be made by chest telerradiography and sputum bacterioscopy by the method of Gram.
. Measles - The pre-exantematic phase (cough, nasal discharge, conjuntivitis) doesn’t occurs in dengue. The morbilliform rash usually begins on the face, with a cefalo-caudal progression. The presence of ‘Koplik’ lesions in the jugal mucous membrane just before the exantematic phase is a pathognomonic sign of measles. A positive vaccination history doesn’t exclude the diagnosis, because an inadequate immunization may have occurred.
. Rubella (German measles) - Fever with an insidious onset, absence of systemic sympyoms and linfoadenomegaly (retroauricular, suboccipital, cervical) preceeding a rash which usually begins on the face are typical of rubella. The diagnosis of rubella cannot be made on clinical basis, but by serologic methods.
. Malaria - Diagnosis is made by detection of Plasmodium forms on serial blood examination. Fever in malaria is initially of daily presentation, and spleen may be enlarged and tender; jaundice may also be present.
. Yellow Fever - The initial clinical manifestations are indistinguishable from dengue. However, the period of incubation usually doesn’t exceed 6 days. Laboratory findings include leukopenia and neutrophilia, a very low erythrocyte sedimentation rate (nearby 0mm) and a marked increase in the serum transaminases levels. A positive vaccination history pratically excludes the diagnosis of yellow fever.
. Meningoencephalitis - Headache, presence of petechiae and shock with an onset < 24 - 48 hours indicate the obrigatory exclusion of meningococcemia (in the severe forms of dengue these manifestations usually occur after the third day of disease). Leukocitosis and neutrophilia, thrombocytopenia and hemoconcentration may be present. Besides, neurologic manifestations tend to be absent in dengue fever, in contrast with meningoencephalitis. The evaluation of the cerebral spinal fluid is the basis of diagnosis, because in dengue fever the CSF is usually normal.
. Pielonephritis - The diagnosis is made based on the urine bacterioscopy by the method of Gram and urinocultures. Urinalysis is inadequate for the evaluation of the urinary tract infections. WBC may show leukocitosis and neutrophilia.
. Septicemy - The onset of symptoms is more insidious and it’s usually possible for the clinician to detect a primary infectious focus. Splenomegaly, leukocitosis/ leukopenia, metabolic acidosis and neurologic disturbances may be present. Related diseases like diabetes mellitus, alcoholism, neoplasms and malnutrition may lead to the correct diagnosis, which is made by hemocultures.
No specific treatment of dengue is available. Early institution of supportive treatment (fluids replacement and correction of electrolyte imbalances) is the key to management of patients with dengue in all its forms, since high fever, anorexia, vomiting and cappilary leakage result in some degree of dehidration.
A. Criteria For Home Observation:
. All cases of dengue fever with no need of intravascular fluids replacement;
. Patients regarded as Grade I capable of receiving oral fluids replacement therapy (OFRT);
. Patients regarded as Grade II capable of receiving OFRT and without important bleedings.
B. Criteria For Short-Duration Admission In Hospital (12 - 24 hours):
. All cases of dengue fever that need intravascular fluids replacement;
. Patients regarded as Grade I without response to OFRT;
. Patients regarded as Grade II without response to OFRT;
. Patients regarded as Grade I or II with hepatic tenderness;
. All patients regarded as Grade III.
C. Criteria For Long-Duration Admission In Hospital (> 24 hours):
. Patients with no response to fluids replacement therapy after short-duration admission;
. Patients regarded as Grade I or II with predisposing factors to develop severe forms of presentation (asthma, alergies, diabetes mellitus, chronic obstructive pulmonary diseases ...)
. Patients regarded as Grade II or III with important bleedings;
. All patients regarded as Grade IV.
Intensive monitoring of vital signs and markers of hemoconcentration, replacement of intravascular volume with lactated Ringer’s solution or isotonic saline , correction of metabolic acidosis, and O2 therapy is life-saving in patients with DSS. Once the patient is stabilized and capillary leakage stops and resorption of extravasated fluid begins, care must be taken not to induce pulmonary edema with continued intravenous fluid administration.
In relation to symptomatic therapy, salicylates should be avoided because of the potential bleeding diathesis and because dengue has been associated with Reye syndrome in a few cases.
As mentioned in section III, with early supportive treatment, the majority of cases recover rapidly and without sequelae. Hospitalized patients can return their houses after 2 days without fever; all patients often experience prolonged convalescence with generalized asthenia and depression lasting several weeks.
- In areas infested with A. aegypti, patients should be safeguarded from mosquito bite;
- Combat against the urban vectors (insecticides, avoid water storages inside and around houses). It’s important to remember that A. aegypti is a domestic mosquito, bites during the morning/ afternoon and has a low fly-autonomy (200 m), different from Culex sp.;
- There’s no vaccine available at the moment, althoug experimental live, attenuated vaccines developed in Thailand against all four serotypes have been tested clinically; various approaches to genetically engineered vaccines are also being explored.
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