Review

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Dengue fever: diagnosis

and treatment
Expert Rev. Anti Infect. Ther. 8(7), 841–845 (2010)

Viroj Wiwanitkit
Wiwanitkit House, 38/167 Soi Yim
Prayoon Sukhapiban, 1 Road
Bangkhae, Bangkok 10160, Thailand
wviroj@yahoo.com
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.

Keywords : dengue • diagnosis • treatment

Dengue is a significant mosquito-borne infec-
tion. An arbovirus named dengue virus is the
causative agent. Due to the nature of the mos-
quito-borne infection, dengue has become a
significant public health threat in many devel-
oping 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 den-
gue 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 trans-
ported, dengue is not confined within the trop-
ical 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 epidemi-
ology 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 epidem-
ics 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 practi-
tioners 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 high-
lights 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 den-
gue 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 unsuccess-
ful 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.

www.expert-reviews.com 10.1586/ERI.10.53 © 2010 Expert Reviews Ltd ISSN 1478-7210 841

 Review Wiwanitkit
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 arbovi-
rus, dengue virus is transmitted by the mosquito vector, Aedes
spp. Aedes aegypti is the main carrier is responsible for approxi-
mately 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 mos-
quito 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 hemor-
rhagic fever is the result of an immune mimicking process between
parts of the dengue virus and the platelet that cause autodestruc-
tion 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 men-
tioned, 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 experi-
ence 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 clini-
cally 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 sim-
ple form of dengue infection, a petechia is the only sign of infec-
tion, 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
842
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 impor-
tant 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 lit-
tle 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 care-
fully, 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 diag-
nostic 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 infec-
tion [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
Expert Rev. Anti Infect. Ther. 8(7), (2010)

in real practice. Also, the problem of quality control and standardi-
zation 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 gen-
erated during the reverse transcription step and, subsequently, ampli-
fied 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 dis-
eases 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 den-
gue 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 suc-
cess 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 emerg-
ing 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 infec-
tion 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] .
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, aim-
ing 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 hospitaliza-
tion. In severe cases of dengue infection, fluid replacement should
be carefully used and must be performed under close observa-
tion in a hospital. Parenteral, intravenous fluid replacement by
either colloids or crystalloids should be considered in order to
prevent shock [51] . 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
www.expert-reviews.com
Dengue fever: diagnosis & treatment Review
by 10 ml/kg/h for 6 h, then the rate can be adjusted accord-
ing to the status of the patient in the following 16 h [52] . 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 [52] . This monitoring should be done for at
least 1 day after the discontinuation of intravenous fluid admin-
istration to prevent possible fluid intoxication in the convalescent
phase due to fluid redistribution.
The preferable new treatment for dengue would be an anti-
viral 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 den-
gue virus has been observed [53] . In modern medicine, ribavirin,
glycyrrhizin and 6-azauridine are reported to have cytostatic and
inhibitory effects on the dengue virus [54] . An adenosine analog
is another promising drug currently being studied. The chemical
‘NITD008’ is the best example [55] .
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 under-
stand 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 [57] .
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 [101] . 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.
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 infec-
tion in tropical medicine. In diagnosis, presumptive clinical diag-
nosis 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.
843
 Review Wiwanitkit

Five-year view Financial & competing interests disclosure

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.
The author has no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.

Key issues
• Dengue has become a widespread infection over the past few year, extending from endemic to nonendemic areas.
• Severe dengue infection can lead to death, therefore, clinicians should should aim for prompt diagnosis and treatment.
• Presumptive diagnosis of dengue is still widely used in the clinical setting.
• Molecular-based diagnosis is the new approach to achieve early diagnosis of infection.
• The main treatment is supportive and symptomatic treatment by fluid-replacement therapy.
• Discovery of a new antiviral drug for dengue is the best hope for treatment.

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