Prevention and treatment of dengue virus infection
By Jamal Panhwar Information source from Alan L Rothman, MD
There have been around 600 confirmed Dengue Virus cases and over 2000 people admitted in hospitals in Pakistan. It is an alarming situation in a country where self medication is very popular and not all the cases are reported specially in the villages and suburbs of Pakistan. It is very Important to educate people about this disease. Special announcements may be made on TV Radio and Mosques for prevention of the disease. The only and most effective precaution is to stay away from the mosquitoes It is very important to put mosquito proof nets on windows stagnant water should be sprayed with carosine oil on weekly basis by the Naib Nazims and Mohala cometees. At home people should also make sure there is no stored wather in un covered containers, mosquito repalent MUST be used while going out and inside the home every effort be taken to get rid of mosquitoes.
Here are some detailed facts about dengue Virus. This important has been extracted for several medical journals.
INTRODUCTION ? Dengue is a febrile illness that is caused by any one of four serotypes of this flavivirus (DEN-1, DEN-2, DEN-3, and DEN-4). It is endemic in more than 100 countries in tropical and subtropical regions of the world and causes an estimated 50 million infections annually worldwide [1-3].
The public health burden of dengue predominantly relates to its most serious manifestations, dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS) [4]. Epidemiologic studies have demonstrated that the greatest risk factor for the development of DHF or DSS is secondary infection with a different dengue serotype from the original infecting virus [5]. Thus, severe disease occurs primarily in patients who reside in hyperendemic areas where multiple serotypes circulate simultaneously.
Dengue virus infection is a risk for anyone living in or traveling in a dengue endemic region, especially in tropical Asia, Central and South America, and the Caribbean. In most of these regions, dengue virus transmission occurs year-round. However, the risk of infection tends to be seasonal and can be expected to be highest during a recognized outbreak of dengue infections. The objectives of programs to prevent dengue infections differ depending upon whether local residents or visitors are targeted. There is no direct therapy available against the dengue virus, which increases the importance of prevention.
Measures to prevent dengue fever and supportive treatment for the complications of dengue virus infection will be reviewed here. The pathogenesis, clinical manifestations, and diagnosis of infection are discussed separately. (See “Pathogenesis of dengue virus infection” and see “Clinical presentation and diagnosis of dengue virus infections”).
PREVENTION ? The greatest risk for dengue virus infection is in individuals residing in endemic areas and not in travelers.
Public health efforts in endemic areas ? Control of the Aedes aegypti mosquito which transmits dengue virus and the development of vaccines are two potential approaches in preventing dengue virus infections.
Mosquito control ? Mosquito control is the most effective approach to the prevention of dengue transmission. Programs targeting the Aedes aegypti mosquito as a means to eliminate urban yellow fever in the Americas from the 1940s through 1970s were quite successful [6]. These programs were also effective at reducing dengue transmission in the region. These programs were based on a “top down” approach involving aggressive mosquito surveillance and insecticide use. However, lack of attention and funding of these programs in the 1970s led to re-emergence of A. aegypti throughout its former region and the corresponding re-emergence of dengue.
Insecticide spraying, in response to dengue outbreaks, is not highly effective against A. aegypti mosquitoes, which frequently breed inside houses [6,7]. Community-based approaches involving education of the population in efforts to reduce breeding sites, such as discarded tires and other containers that accumulate standing water, have shown some promise [6].
A comprehensive community and governmental control strategy, including the seeding of water vessels with copepods that feed on mosquito larvae, has been successful in eliminating A. aegypti and dengue transmission in 32 communities in rural areas of Vietnam [8]. However, this strategy will be more difficult to apply in cities where breeding sites are different and community participation may be harder to sustain [9].
Vaccination ? Infection with dengue provides long-term protection against the particular serotype that caused the disease, supporting the feasibility of a dengue vaccine. However, it provides only short-lived immunity to the other three dengue serotypes. In view of the association of DHF with previous exposure to dengue viruses and the recognition that all four serotypes are capable of inducing DHF it is the general consensus in the scientific and public health communities that any candidate vaccine should produce protective immunity against DEN 1-4. Since waning immunity might also increase the risk for DHF in vaccinees, vaccine-induced protective immunity should also be long-lived.
Animal studies indicate that protective immunity against dengue can be mediated by neutralizing antibodies, especially those directed against the envelope (E) glycoprotein. However, natural dengue infection induces low levels of cross-reactive antibodies that are detected in neutralization assays, but do not prevent infection with the other dengue serotypes [10]. This cross-reactivity will further complicate the laboratory assessment of vaccine-induced immunity.
A tetravalent vaccine that induces immunity against all four serotypes is in development. In a rhesus monkey model, a tetravalent live attenuated dengue virus vaccine demonstrated seroconversion rates of 100, 100, 90 and 70 percent against dengue serotypes 1,2,3, and 4 [11]. In addition, vaccination resulted in complete protection against viremia from inoculation with serotype 2; protection against challenge with the other dengue serotypes resulted in protection in 50 to 80 percent of animals compared to controls.
To date, there is no licensed vaccine available for preventing dengue. Several live attenuated tetravalent vaccines have entered clinical testing, and preliminary data are encouraging with regard to reactogenicity and immunogenicity in adults and children [12-14]. Interference in replication between the four component viruses has been problematic, leading to skewing of the antibody and cellular immune responses. The need for adjustment of the vaccine formulations and multi-dose vaccination regimens has slowed clinical testing of these vaccines as well. As a result, data on vaccine efficacy and persistence of immune responses are lacking [10].
Recommendations for travelers ? Most travelers from non-endemic countries are at exceedingly low risk for DHF because they lack previous exposure to dengue viruses (see “Pathogenesis of dengue virus infection”). Possible exceptions include immigrants from endemic areas subsequently returning to their countries of origin and frequent international travelers. Regardless of the risk for DHF, most travelers will wish to avoid the morbidity of dengue fever.
Avoidance of exposure to infected A. aegypti mosquitoes is the primary approach to prevention of dengue virus infections in travelers. These mosquitoes predominantly live in urban areas in and around houses [7]. Thus, travelers to major cities are at risk for exposure to A. aegypti. Bed netting is of little use since the mosquitoes are most active during the daytime [15]. Remaining in well-screened or air-conditioned buildings during the day can reduce the risk of exposure but many travelers are unwilling or unable to comply. When outside during the day, travelers wishing to avoid dengue should wear clothing that reduces the amount of exposed skin and should use an effective mosquito repellent, such as N,N-diethyl-metatoluamide (DEET).
THERAPY ? Since, as noted above, there is no specific therapy available for dengue virus infections, it is important to exclude other treatable diagnoses. Patients at risk for dengue can acquire other diseases with similar clinical features, such as malaria, typhoid fever, and leptospirosis. Symptoms in patients with dengue virus infections resolve in five to seven days.
Supportive treatments are available for the specific disease manifestations of dengue virus infection.
Dengue fever ? Patients with dengue fever should be cautioned to maintain their intake of oral fluid to avoid dehydration. Fever and myalgias can be managed as needed with acetaminophen. Aspirin or nonsteroidal antiinflammatory agents should generally be avoided because of the risk of bleeding complications and in children because of the potential risk of Reye’s syndrome. The most important measure to assist the patient with dengue fever is to carefully evaluate the patient for impending complications, such as early evidence of DHF, as described below.
Dengue virus infection with significant bleeding ? Gastrointestinal bleeding or menorrhagia in patients with DHF, and occasionally in patients with dengue fever as well, can be severe enough to require blood transfusion. Factors that contribute to bleeding include thrombocytopenia due to decreased platelet survival [16] and, in severe cases, frank disseminated intravascular coagulation. (See “Pathogenesis of dengue virus infection”). Platelet transfusions are rarely given, but may be warranted in patients with severe thrombocytopenia (<10,000/mm3) and active bleeding.
Dengue hemorrhagic fever ? Plasma leakage in DHF is important to manage with aggressive intravascular volume repletion to prevent or reverse hypovolemic shock [17]. In mild cases, particularly when medical attention is received early, oral rehydration may be sufficient. However, in patients with established intravascular fluid loss, intravenous fluid administration is recommended. Blood transfusion is appropriate in patients with significant bleeding; subsequent hematocrit measurements must be interpreted with caution since it is also critical to assess the adequacy of fluid repletion.
Treatment of shock ? A protocol for intravenous fluid therapy has been developed by the World Health Organization (WHO) based upon clinical experience mainly in children from Southeast Asia [18]. For patients with shock, an initial bolus of five percent dextrose in normal saline or Ringer’s lactate (10 to 20 mL per kg of body weight) infused rapidly is recommended, followed by continuous infusion (10 to 20 mL/kg per hour) until vital signs and urine output normalize. The infusion rate can then be gradually reduced until it matches plasma fluid losses.
There has been debate as to whether crystalloids or colloids should be used for volume replacement in critically ill patients. Three randomized, blinded trials have investigated the effect of different fluid regimens on outcome [19-21]. The largest of these studies was a double-blind randomized comparison of three fluids for initial resuscitation of 512 Vietnamese children with dengue shock syndrome [21]. Three hundred eighty-three patients with moderate shock were assigned to Ringer’s lactate or one of two different colloid solutions: six percent dextran 70 or six percent hydroxyethyl starch. One hundred twenty-nine patients with severe shock were randomized to receive one of the two colloids. The treatment regimen closely followed the WHO protocol above, with 15 mL/kg administered over the first hour and 10 mL/kg over the second hour. Only one patient died. This trial established that Ringer’s lactate was a safe, effective, and inexpensive alternative in initial resuscitation of patients with moderate shock. In patients with severe shock, dextran and starch performed similarly, although dextran was associated with more hypersensitivity reactions.
The adequacy of fluid repletion should be assessed by serial determination of hematocrit, blood pressure, pulse, and urine output. Patients with shock on presentation should initially have vital signs measured at least every 30 minutes and hematocrit measured every two to four hours. Narrowing of the pulse pressure is an indication of hypovolemia in children even with a normal systolic blood pressure. Normalization of the hematocrit is an important goal of early fluid repletion; however, a normal or low hematocrit may be misleading in patients with overt bleeding and severe hypovolemia. (See “Treatment of severe hypovolemia or hypovolemic shock in adults”).
Close clinical observation is essential, even after normal blood volume is restored, because patients can develop shock for one to two days after initial fluid resuscitation which represents the period of increased vascular permeability in DHF. Most patients who present for medical attention before profound shock develops and who receive appropriate fluid therapy will recover quickly.
The fluids that are lost into tissue spaces during the period of plasma leakage are rapidly reabsorbed. Thus, intravenous fluid supplementation should be discontinued once patients are taking oral fluids and have normal hematocrit, vital signs, and urine output. Usually no more than 48 hours of intravenous fluid therapy are required. Excessive fluid administration after this point can precipitate hypervolemia and pulmonary edema.
In the absence of complications from prolonged hypotension or from medical interventions, most patients with DHF will have stabilized within a few days of admission. Discharge from the hospital is appropriate when patients have been afebrile for at least 24 hours and have normal oral intake, urine output, and hematocrit.
The basis of DHF pathogenesis is hypothesized to be immunologic, which has led to interest in immunomodulatory drugs for therapy. (See “Pathogenesis of dengue virus infection”). However, a meta-analysis of four trials involving 284 participants found that corticosteroids were no more effective than placebo in reducing the number of deaths, the need for blood transfusion, or the number of serious complications [22].
Unusual complications ? Encephalopathy and liver failure are uncommon manifestations of DHF which are associated with a high mortality rate [23]. While seizures or jaundice should always be regarded as indicative of severe disease, no specific treatment is available.
Outpatient management and early recognition of DHF ? Because dramatic plasma leakage can develop suddenly, substantial attention has been placed upon the early identification of patients at higher risk for shock and other complications. The following clinical features are helpful in this determination:
????????????????????????????????? Duration of illness ? The period of maximum risk for shock is between the third and seventh day of illness. This tends to coincide with resolution of fever. Plasma leakage generally first becomes evident between 24 hours before and 24 hours after defervescence.
????????????????????????????????? “Alarm signs” ? Severe abdominal pain, persistent vomiting, abrupt change from fever to hypothermia, or abnormal mental status, such as disorientation, are noted in a minority of patients [24]. In one study, these signs developed less than one day prior to hospitalization.
????????????????????????????????? Hematocrit ? An elevation of the hematocrit is an indication that plasma leakage has already occurred and that fluid repletion is urgently required.
????????????????????????????????? Platelet count ? Severe thrombocytopenia (<100,000/mm3) is one of the clinical criteria for DHF and usually precedes overt plasma leakage.
????????????????????????????????? Serum aspartate transaminase (AST) ? Mild elevations in serum transaminases are common in both dengue fever and DHF. However, levels are significantly higher in patients with DHF, and elevated AST levels are noted earlier in illness than the other signs listed above. In one study conducted in Thailand, a normal AST level was a strong negative predictor of DHF (negative predictive value 0.96) even in the first three days of illness [1].
????????????????????????????????? Soluble dengue NS1 protein ? Blood levels of soluble dengue NS1 protein (> 600 mg/mL) were predictive of DHF in one study of Thai children with secondary dengue 2 virus infections [25]. Another assay that measures blood soluble dengue NS1 levels has become commercially available outside the United States; if the clinical utility of this commercial assay is similar to the published data, measurement of soluble dengue NS1 protein may become a clinically useful parameter for patient management.
Patients with suspected dengue who do not have any of the above indicators can be safely managed as outpatients as long as close clinical observation is assured. Daily outpatient visits may be needed to permit serial assessment of blood pressure, hematocrit, and platelet count. One study in Malaysia over a two month period tested a standard treatment protocol for patients with suspected dengue [26]. Daily outpatient visits were conducted and referral for hospitalization was made only for one of the following signs:
????????????????????????????????? Blood pressure <90/60 mmHg
????????????????????????????????? Hematocrit >50 percent
????????????????????????????????? Platelet count <50,000/mm3
????????????????????????????????? Evidence of bleeding other than petechiae
There were no deaths among 162 adults studied (average age 27 years), of whom 28 (17 percent) had DHF; the overall hospitalization rate was 44 percent. All of the subjects with DHF either were hospitalized or qualified for hospitalization according to the protocol, whereas 89 (66 percent) of the subjects without DHF were managed without hospitalization.
For many resource-poor dengue endemic countries, routine laboratory testing is not readily available. One study of 1250 children aged 2 months to 10 years presenting to a pediatric hospital in southern Vietnam evaluated whether an assessment tool designed for first level health care workers, using only clinical signs, could appropriately classify and guide management of acute illnesses in an endemic area [27]. The assessment tool was derived from the WHO/UNICEF “Integrated Management of Childhood Illness” algorithm designed for use in Africa and was modified to include common signs and symptoms of DHF. Although the 20 children with established dengue shock syndrome were correctly identified as requiring urgent hospitalization, classification of less severe DHF was imperfect and reevaluation within one to two days was needed to detect children who developed shock.
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