Dengue Fever: Diagnosis and Treatment

Viroj Wiwanitkit
Authors and Disclosures
Posted: 08/18/2010; Expert Rev Anti Infect Ther. 2010;8(7):841-845. © 2010 Expert Reviews Ltd.

Abstract

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.

Introduction

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.[1] 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.[2] 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.[3] Dengue infection has also been reported in nontropical regions of Asia,
such as East Asia and China.[4] 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.[5] Similarly, dengue infections also already extend to Australia and
dengue has been accepted as a significant emerging infection of concern in Australia.[6] Outbreak of
dengue infection in North Queensland gave great concern to the local CDC.[7] In Queensland, it is advised
that general practitioners report all clinically suspected cases of dengue in any arriving travelers.[8] 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.[18] 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.[19] 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.[20] 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,[21] 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.[27]

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[28]) 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.[33] 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.[28]
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.[34]Cao et al. mentioned that the tourniquet test was a helpful indication of dengue
infection in diagnosis in highly rural areas in endemic countries.[34] 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.[35] 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.[36]

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".
[38]
Identification and quantification of distinct dengue virus strains and serotypes in clinical samples (most
preferably serum[39]) can be performed by PCR-based techniques.[37]

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.[42] 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.[44] 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[45] can be upgraded into the nanofluidic system by adjustment of the internal
electromagnetic system.[46] Combining nanotechnology with molecular diagnostic techniques may be the
key to success in the development of a new nanofluidic system for dengue virus determination.
[47]
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.[48] 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'.[49] 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.[50

Conclusion

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.

Expert Commentary

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.

Five-year View

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.