Dengue Fever: Diagnosis and Treatment
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Dengue fever is a common tropical infection. This acute febrile illness can be a deadly infection in cases of severe manifestation, causing dengue hemorrhagic shock. In this brief article, I will summarize and discuss the diagnosis and treatment of this disease. For diagnosis of dengue, most tropical doctors make use of presumptive diagnosis; however, the definite diagnosis should be based on immunodiagnosis or viral study. Focusing on treatment, symptomatic and supportive treatment is the main therapeutic approach. The role of antiviral drugs in the treatment of dengue fever has been limited, but is currently widely studied.
Dengue is a significant mosquito-borne infection. An arbovirus named dengue virus is the causative agent. Due to the nature of the mosquito-borne infection, dengue has become a significant public health threat in many developing tropical countries. Dengue had been present throughout tropical regions of the world for more than 50 years. Of several tropical regions, Southeast Asia is accepted as the area with the highest prevalence of this disease. A severe hemorrhagic form of dengue infection has become a leading infectious cause of death for local people in Southeast Asia. Francisco Pinheiro, a former researcher from the Division of Disease Prevention and Control, and the Special Program for Vaccines and Immunization, Pan American Health Organization (DC, USA), said that the highest incidence of dengue could be seen in Southeast Asia, particularly in Vietnam and Thailand, which together account for more than two-thirds of the overall reported cases in Asia. Hence, several groups are now carrying out research and development on dengue infection in this area.
At present, due to the efficient mosquito-borne method by which the virus is transported, dengue is not confined within the tropical region, but is sporadically reported from many nontropical countries. It is accepted that it is now a global issue. In South Asia, there have been many reports of dengue epidemiology coming in from India. An increased incidence among the pediatric population in the over-populated areas can be seen. Dengue infection has also been reported in nontropical regions of Asia, such as East Asia and China. Luo et al. noted that epidemics of dengue fever are closely related to the situation of neighboring countries, especially those is Southeast Asia. This indicated the possibility of importation of viruses from these countries, with the epidemics usually arising due to immigration of dengue patients from endemic areas. Similarly, dengue infections also already extend to Australia and dengue has been accepted as a significant emerging infection of concern in Australia. Outbreak of dengue infection in North Queensland gave great concern to the local CDC. In Queensland, it is advised that general practitioners report all clinically suspected cases of dengue in any arriving travelers. For Africa, America,[9-11] Europe[12-14] and Africa[15-17] the increase in reported cases of dengue highlights the necessity to prepare to combat this viral disease.
Focusing on the natural characteristics of dengue, this acute febrile illness can be deadly in cases of severe manifestation, causing dengue hemorrhagic shock. Patients usually visit the physician on the second or third day after the first appearance of fever, and after self-treatment of the illness by some self-prescribed antipyretic drugs. However, after unsuccessful self-treatment, the patients usually end up visiting the physician with a chief complaint of an unexplained high fever and malaise. In this brief article, I will summarize and discuss the diagnosis and treatment of this disease.
Pathogenesis, Natural History & Clinical Manifestation of Dengue
Before the diagnosis and treatment, the pathogenesis, natural history and clinical manifestation of dengue should be discussed. As previously mentioned, the pathogenic agent for dengue is an arbovirus namely 'dengue virus'. There are four serotypes of dengue virus that can be seen around the world. As an arbovirus, dengue virus is transmitted by the mosquito vector, Aedes spp. Aedes aegypti is the main carrier is responsible for approximately two-thirds of the world's dengue. Hence, there is no doubt that when dengue virus is carried to a new setting, further transmission by local mosquitos can easily occur. Focusing on epidemiology, the important bioecological parameters that can promote worldwide transmission of dengue include the nature of the A. aegypti-to-human contact, the susceptibility of the mosquito and the method of transmission. These factors can vary across different areas and are important determinants to take into account in areas of dengue emergence.
Focusing on the pathogenesis of dengue, a pattern of acute viral infection can be seen. Generally, dengue is classified as a blood infection and the main reaction of the human body to dengue virus can be seen in the circulation. Due to its nature as a viral infection, lymphotropic phenomenon can be seen; the stimulation of lymphocytes results in lymphocytosis with atypical lymphocyte reactions. Also, disturbance of hemostasis is another important pathological process in dengue infection. The infection causes vascular leakage as well as platelet destruction, which, in severe cases, results in thrombocytopenia and bleeding. The cause of thrombocytopenia in dengue is thought to be an immune-related process;[22,23] the destruction of the platelet in dengue hemorrhagic fever is the result of an immune mimicking process between parts of the dengue virus and the platelet that cause autodestruction of the platelet by IgM.[24-27] Hence, the self limitation of platelet destruction after the acute phase of infection can be seen in the natural history of dengue.
Concerning the natural history of dengue, as previously mentioned, an incubation period of 5-8 days followed by the onset of a high-peak fever, headache, malaise and myalgia with a rash developing after 3-4 days is common. Generally, most dengue infections are classified as simple dengue fever. The affected patients usually present with high fever (almost all cases) and present a positive tourniquet test.[29-31] The fever usually lasts 4-7 days due to the nature of viral infection. Most patients experience a complete recovery without complications;[29-31] however, a number of atypical forms of clinical manifestation can be seen. These atypical infections can manifest without fever or clinically serious symptoms,[29-31] and gastrointestinal and respiratory symptoms can be detected.[28,32]
Focusing on the serious form of dengue, the forms with overt bleeding (dengue hemorrhagic fever) and shock (dengue shock syndrome) are classified as dengue with high severity. In the simple form of dengue infection, a petechia is the only sign of infection, seen after application of the tourniquet test. However, if severe infection occurs, high morbidity and mortality can be expected if appropriate treatment is not administered. An important step in the management of dengue is monitoring severe forms of infection. It is observed that hematocrit progressively increases and platelet count progressively decreases from simple dengue to dengue shock syndrome, presumably due to increasing hemoconcentration.
What is New in Diagnosis of Dengue?
Generally, the diagnosis in many endemic countries is usually a presumptive diagnosis via clinical evidence of acute febrile illness with decreased platelet count. The tourniquet test is an important basic screening test for dengue. The WHO also suggests using the tourniquet test as a vital parameter in the diagnosis of dengue. Cao et al. mentioned that the tourniquet test was a helpful indication of dengue infection in diagnosis in highly rural areas in endemic countries. The main reason for this practice is the limited resources and the fact that there is little change in therapeutic management after receiving a definite diagnosis method.
Focusing on the present definitive diagnosis, the immunological-based test or viral study can be applied. However, due to the complex process involved in isolating the virus, viral study is rarely performed and the immunological-based test is more widely used. Although the immunological-based test does not significantly change the management of the infected case, it is useful for epidemiological records and disease-control planning. Hemaglutination inhibition, neutralization, and IgM and IgG ELISA assays are examples of immunological-based tests used for definitive diagnosis of dengue. However, the interpretation of the test results has to be done carefully, relating to the timing of serum collection. Also, since most patients do not visit the physician during the early stages of the disease, and the chance of following up with a serological test is commonly lost, a new, more rapid test for diagnosis of dengue is required. Of interest, Schilling et al. discussed the need to combine IgM antibody detection with the detection of virus or viral RNA using real-time PCR for early diagnosis of dengue.
Molecular Diagnostic Tool for Dengue
As mentioned earlier, the trend of using a molecular-based diagnostic tool such as PCR-based test kits has become the new approach for early diagnosis of dengue. There have been many reports recently on using PCR techniques for diagnosis of dengue. Most of these reports usually mention its use in the rapid and effective diagnosis of dengue at the very early phase of infection.[37,38] De Paula et al. suggested that, "RT-PCR is definitely the most satisfactory test that can be used on these infections, since it has been shown to be able to detect dengue viruses up to the tenth day after the onset of the symptoms". Identification and quantification of distinct dengue virus strains and serotypes in clinical samples (most preferably serum) can be performed by PCR-based techniques.
However, the big problem in implementing these PCR-based techniques for real-life use in endemic areas in developing countries is the cost of the test kits. It is advisable that further studies should be performed to verify the cost-effectiveness of using PCR-based techniques compared with classical presumptive diagnosis of dengue in real practice. Also, the problem of quality control and standardization of molecular-based diagnostic test kits for dengue should be considered.[40,41] False positives may be generated in vitro when using the PCR-based tests, since falsely primed cDNAs may be generated during the reverse transcription step and, subsequently, amplified by PCR. Specific international control and validation of the currently used test kits is suggested to avoid this problem.[40,41,43]
Nanodiagnostic Tools for Dengue
Nanodiagnosis is the new challenge in laboratory medicine; the application of nanodiagnostic tools for diagnosis of tropical diseases is the present focus in tropical medicine. At present, there have been several attempts to develop new nanodiagnostic tools for dengue; however, to date, no launched diagnostic test kit has been launched. Indeed, the microfluidic system for dengue detection that has been reported in the literature can be upgraded into the nanofluidic system by adjustment of the internal electromagnetic system. Combining nanotechnology with molecular diagnostic techniques may be the key to success in the development of a new nanofluidic system for dengue virus determination. Additionally, the use of nanomaterial to enhance the immunological reaction, thereby allowing visibility of the presence of the virus with the naked eye to help ease the diagnostic procedure, is another important aim in diagnostic test kit development.
Point-of-care Testing for Dengue Diagnosis
A new challenge in point-of-care technology is the development of diagnostic tests that can be applied for use against emerging infections. Some patents have recently been granted for such point-of-care tests (such as WO/2009/139725). However, although dengue is considered a problematic emerging infection in many settings, there are only a few point-of-care testing products for dengue diagnosis avaliable. Recent development in dengue diagnosis is the nonstructural one-antigen test or 'NS1 test'. There are some commercial products, either ELISA or rapid strip assay, that have been evaluated for clinical diagnosis. The immunochip produced by Wu et al. is the best example.
What is New in Treatment of Dengue?
Given that dengue is an infection, treatment can be performed using the simple concept of 'getting rid of the pathogen and limiting the complications'. In general, the use of supportive and symptomatic treatment is widely used for dengue treatment, aiming to limit the complications of the infection. The application of fluid therapy has become key in dengue management and this is applied based on the severity of disease. In simple dengue, oral fluid replacement is sufficient and there is no need for hospitalization. In severe cases of dengue infection, fluid replacement should be carefully used and must be performed under close observation in a hospital. Parenteral, intravenous fluid replacement by either colloids or crystalloids should be considered in order to prevent shock. The basic recommendation for intravenous fluid-replacement therapy is administration of 0.9% normal saline solution at a rate of 20 ml/kg/h in the first 2 h, followed by 10 ml/kg/h for 6 h, then the rate can be adjusted according to the status of the patient in the following 16 h. Water and electrolyte status should be maintained during treatment to avoid under and over administration of fluid. A basic follow-up laboratory test should be used to evaluate the hematocrit and platelet count. It is noted that a progressive rise in hematocrit with a progressive reduction of platelet count implies a high risk for developing shock. This monitoring should be done for at least 1 day after the discontinuation of intravenous fluid administration to prevent possible fluid intoxication in the convalescent phase due to fluid redistribution.
The preferable new treatment for dengue would be an antiviral drug. At present, a specific antiviral drug is not available; however, there have been a lot of attempts to discover one. In phytomedicine, several sulfated polysaccharides extracted from seaweeds have been studied and high antiviral activity against dengue virus has been observed. In modern medicine, ribavirin, glycyrrhizin and 6-azauridine are reported to have cytostatic and inhibitory effects on the dengue virus. An adenosine analog is another promising drug currently being studied. The chemical 'NITD008' is the best example.
The use of computational biology, bioinformatics and high-throughput screening can be helpful for searching of new antiviral drug for dengue.[56-58] This technique helps identify and understand the molecular structure of dengue for prediction of binding to the newly developed drug. For example, Freser and Miertus screened a combinatorial library of peptidomimetic inhibitors of dengue virus NS2B-NS3 protease via the described in silico technique.
In addition to the antiviral drug, it is also useful to discuss the new guidelines published by the WHO and the Special Programme for Research and Training in Tropical Diseases. Based on this publication, the new classifications of dengue disease are: dengue without warning signs (i.e., abdominal pain, persistent vomiting and clinical fluid accumulation), dengue with warning signs and severe dengue (i.e., severe plasma leakage, severe hemorrhage and severe organ impairment). This classification system aids earlier detection of complicated cases; however, the principles of dengue management are still concordant with those discussed earlier.
Dengue virus is a currently a problematic global infection. Diagnosis via new molecular-based techniques have become a new hope for early diagnosis, but are still limited due to their costs and standardization. The possibility of treatment of dengue via antiviral drugs is still under investigation.
It is important to know how to diagnose and treat dengue infection in tropical medicine. In diagnosis, presumptive clinical diagnosis of dengue is, at present, still useful. Further development of new efficient and inexpensive diagnostic tool kits will be useful. In treatment, supportive and symptomatic treatment is the key practice. The ongoing research on antiviral drugs might be the clue to better treatment.
Within the next 5 years, dengue will still be a prominent viral infection. The new standardized diagnostic tool kits, including molecular-based, nanodiagnostic and point-of-care testing tool kits will be useful in diagnosis of infection. New antiviral drugs will become available and aid in the management of dengue infection in the next 5 years.
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