PRIMARY CARE MANAGEMENT OF DENGUE/DENGUE HAEMORRHAGIC FEVER DURING AN OUTBREAK
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PRIMARY CARE MANAGEMENT OF DENGUE/DENGUE
HAEMORRHAGIC FEVER DURING AN OUTBREAK
ADVISORY BY THE CFPS DENGUE WORKGROUP
Date of issue: 1 October 2005
INTRODUCTION
Objective
The objective of this advisory is to provide
a collation of information for family
physicians who face the challenge of
managing patients in the early and
undifferentiated phase of the illness.
Please supplement the information with
updates from the Ministry of Health and
other information as these become
available.
GENERAL CONSIDERATIONS
Epidemiology
Present situation
Dengue infection is endemic in Singapore
with new cases reported throughout the
year. The majority of cases are acquired
locally (99%). The majority of those
infected are age 15 and above. The Footnote: Weekly cases as at 19 September 2005. Weekly updates
are available at http://www.moh.gov.sg/corp/publications/idbulletin
highest incidence is among young adults in
the 15 to 24 years age groups. Children
under age of 5 have the lowest incidence. 1
weeks. Infected mosquitoes can pass on
The vector the virus to the next generation of
The bite of Aedes mosquitoes (mainly mosquitoes by transovarian transmission
Aedes aegypti) infected with the dengue (vertical transmission) but this is
virus transmits the disease. The dengue considered rare and does not contribute
virus is therefore an arthropod-borne virus significantly to human transmission.
or arbovirus. The mosquito becomes
infected when it feeds on an infected host Aedes aegypti is one of the most efficient
that has viraemia, usually during the time transmitters of arboviruses because it lives
of the fever. The virus develops in the in close proximity to humans, often
mosquito for about 8 to 10 days where the indoors. This species of mosquito is
virus migrates to the salivary glands. difficult to eradicate because its eggs can
After this period of time, the mosquito withstand dessiccation for as long as a year.
becomes a vector that can transmit the
virus. Once infected the mosquito remains Aedes aegypti is a day-biting species with
infected for the duration of its life span increased biting activity for 2 hours after
which is estimated to be about 2 to 4 sunrise and several hours before sunset. It
1is a domestic breeder and breeds in water immune system to attack it as if it was the
containers, discarded tyres, coconut shells, first subtype.
and overhead tanks.
The immune system is tricked because the
Pathophysiology 4 subtypes have very similar surface
antigens. The antibodies bind to the
Dengue virus surface proteins but do not inactivate the
Dengue (DF) and dengue hemorrhagic virus. The immune response attracts
fever (DHF) are caused by one of four numerous macrophages, which the virus
closely related, but antigenically distinct, proceeds to infect because it has not been
virus serotypes (DEN-1, DEN-2, DEN-3, inactivated. This situation is referred to as
and DEN-4), of the genus Flavivirus. Antibody-Dependent Enhancement (ADE)
of a viral infection. This makes the viral
Immunity infection much more acute. The body
Infection with one of these serotypes releases cytokines that cause the
provides immunity to only that serotype endothelial tissue to become permeable
for life, so persons living in a dengue- which results in hemorrhage and plasma
endemic area can have more than one loss from the blood vessels.
dengue infection during their lifetime. If
an individual develops immunity to one Increased vascular permeability leads to
subtype and then tries to launch an plasma loss from the vascular
immune response to another subtype then compartment. This results in
they will develop DHF/DSS. Work has haemoconcentration, low pulse pressure.
been done on a tetravalent vaccine that When the plasma loss becomes critical,
will attempt to give the individual shock ensues.
immunity to all four of the subtypes at the
same time. Both quantitative and qualitative platelet
defects can develop. Therefore bleeding
Mechanism of complications time can be prolonged even when platelet
It is useful to understand why certain counts are above 100,000 per cubic
individual develop DHF/DSS. The Dengue millimeter.
virus has been shown to have 4 subtypes.
These 4 subtypes are different strains of In the liver there is focal necrosis of
dengue virus that have 60-80% homology hepatocytes, swelling, appearance of
between each other. The major difference Councilman bodies and hyaline necrosis of
for humans lies in subtle differences in the Kupffer cells.
surface proteins of the different dengue
subtypes.
CLINICAL DIAGNOSIS
After a person is infected with dengue, he
or she develops an immune response to Clinical features help the doctor to make a
that dengue subtype. The immune decision on the likelihood that a febrile
response produces specific antibodies to illness will be self-limiting or will
that subtype's surface proteins that prevent deteriorate into a potentially life
the virus from binding to macrophage cells threatening situation. Bearing in mind that
(the target cell that dengue viruses infect) illnesses can have atypical presentations,
and gaining entry. However, if another making a diagnosis is a challenging task
subtype of dengue virus infects the that requires knowledge, skills, experience
individual, the virus will activate the and deductive thinking.
2Clinically dengue infection presents as a and hence is referred to as “saddle-
spectrum of clinical syndromes ranging backed”.
from the asymptomatic to the very severe. Headache, backache, myalgia.
Headache can be severe. There is
(1) Asymptomatic retro-orbital pain. Pain in the muscles,
Many infected individuals remain bone and joints may also be prominent,
asymptomatic. This may be one reason hence it is referred to in the Chinese
why dengue remains endemic and makes language as “the bone pain and blood
isolation of cases ineffective. The fever syndrome”.
percentage of patients who are Rash: maculopapular or flush;
asymptomatic is uncertain: petechiae with islands of sparing.
A two-year study using a cluster There may be nausea and vomiting.
investigation method was conducted in Thrombocytopenia.
West Jakarta, Indonesia to demonstrate
the detection of dengue cases prior to Complications: Dengue fever can be
onset of clinical illness. Among 785 accompanied by bleeding complications
adult and child volunteers enrolled, 17 such as epistaxis, gum bleeding, hematuria
(2.2%) post-enrollment dengue (PED) and even menorrhagia. It can also result in
infections were identified. Eight PED severe life-threatening gastrointestinal
cases were asymptomatic and nine bleeding especially among patients who
were symptomatic.2 are already at risk of developing
In another study dengue gastrointestinal bleeding. The
seroconversion was tested among 104 pathophysiological process of such
Israeli young adults who traveled to bleeding complications is probably
tropical countries for at least 3 months. different from that of dengue hemorrhagic
Seven seroconverted during travel; fever.
four had immunoglobulin IgM
antibodies; one was symptomatic with (4) Dengue Hemorrhagic Fever (DHF)
borderline IgM and a rise in IgG; two There are 4 major clinical features that
others (1.9%) had a rise in IgG titers, define dengue hemorrhagic fever (DHF):
without detectable IgM. Of the four Fever. The fever is high plus
with IgM, three had fever. Out of the 3 Bleeding manifestations (e.g. petechie,
febrile cases, two had chills, headache, ecchymosis, epistaxis, gum bleeding,
and protracted fatigue. One patient had heametemssis, melena) plus
an asymptomatic infection..3 Thrombocytopenia (20% above baseline; Pleural
with an undifferentiated febrile illness effusion; Hypoalbuminaemia)
sometimes accompanied by a non-specific
maculopapular rash. Older children and Neurological disturbances (e.g., seizures,
adults may have just a mild febrile illness. cranial nerve signs and coma) may also
occur.
(3) Dengue Fever (DF)
This is the classic severe febrile syndrome Children with DHF present with a
that is recognized as dengue infection. characteristic syndrome. The fever usually
The clinical features are: rises suddenly accompanied by flushing of
Fever: acute onset, lasts 2-7 days. the skin. The fever is usually high (> 39
Onset of fever is abrupt and rises degree Celsius). It usually remains high
rapidly. It sometimes has two peaks
3for 2 to 7 days. Febrile fits can occur in liver may be tender and is not usually infants and younger children. associated with jaundice. Constitutional symptoms similar to DF (5) Dengue shock syndrome (DSS) such as loss of appetite, vomiting, nausea, All the above plus headache, myalgia, arthralgia, bone pain Evidence of circulatory failure usually comes with the fever. The manifested by hypotension, narrowed conjunctival may become injected. pulse pressure (
uneventful. Good prognostic signs are phenomenon. The patient may have
return of appetite and good urine output. developed DHF.
Case fatality ratio (CFR): This is high in Rising hematocrit and falling platelet
DHF and DSS and in untreated or count
mistreated shock cases have been as high This is detectable in primary care
as 40-50%; with good physiological fluid monitoring of blood investigations. They
replacement therapy, rates should be about indicate development of DHF. This
3.5%. CFR is low in dengue fever by itself. pheonomenon tends to occur just before
the subsidence of fever and the onset of
shock.
RED FLAGS
Subsiding fever with increasing distress
Family physicians are often in a situation In DHF, the critical phase of illness often
where they have to identify the potentially occurs at the end of the febrile period.
serious cases amongst large numbers cases After days of fever, a rapid fall in
in their early and undifferentiated stage of temperature may be accompanied by signs
the disease. A helpful strategy is to of circulatory failure of variable levels of
identify red flags which are situations distress.
where extra caution is needed. In a dengue
outbreak, the following can be red flags: The unusual and the elderly
Dengue can present atypically like an
Abdominal Pain encephalitis, as alcalculous cholecystitis,
Nonspecific complaints of epigastric and severe vomiting or diarrhea, or as
generalized abdominal discomfort are not fulminant hepatitis. Also, the elderly are
uncommon. However acute abdominal more likely than youths and younger
pain is a frequent complaint shortly before adults to develop severe illness. Their
the onset of shock. When it occurs just clinical evaluation must include a careful
around the time of the fever subsiding, assessment for increased capillary
suspicion must be raised. permeability and occult haemorrhage in
order to avoid complications from delayed
Narrow Pulse Pressure identification and treatment of severe
A narrow pulse pressure may be an early dengue infection.5
detectable sign of circulatory disturbance
in dengue infection. MANAGEMENT STRATEGY
Hepatomegaly Investigations at the primary care level
There is no correlation between severity of The strategy for investigation at the
illness and size of a palpable liver. primary care level is directed mainly
However a palpable liver is more likely to towards determining the likelihood that a
be present in shock than non-shock cases. febrile illness is a dengue infection. If
dengue is provisionally diagnosed the
Bleeding phenomenon main purpose of investigations is then to
Bleeding phenomenon to watch out for determine the likelihood of the
and to monitor are epistaxis, bleeding development of complications of
gums, gastrointestinal bleeding and circulatory failure and hemorrhagic
menorraghia. Presence of easy bruising, phenomenon and whether the patient
petechiae and a positive tourniquet test requires hospitalization.
indicate the presence of hemorrhagic A system should be in place for blood
investigation results to be reviewed as
5early as possible because delay in acting Isolation of the virus is the most definitive
on abnormal results can have adverse approach, but presently such tests are more
consequences. suitable for tertiary and research centres
Daily total white cell count and platelet Serological tests are simpler and more
count rapid, but cross-reactions with antibodies
Leucopenia helps in the clinical diagnosis to other flaviviruses may give false
of dengue fever. Platelet count helps in positive results. In addition, accurate
the monitoring of patients for the identification of the infecting dengue virus
development of complications. A platelet serotype is not possible with most
count of < 80,000 cells per cubic mm is a serological methods. Specimen for
criteria for hospital referral and admission. serological tests should be collected in the
Apart from absolute numbers, trends and following manner:
clinical correlations should be taken into • Collect a specimen as soon as possible
consideration. A rising hematocrit and after the onset of illness or attendance
falling platelet counts is ominous. at a clinic (acute serum).
• Collect a specimen shortly before
Hematocrit discharge from outpatient follow-up or
A base line level should be established the hospital or, in the event of a
early in the patient encounter. A rise in fatality, at the time of death
hematocrit ≥ 20% above baseline is a (convalescent serum).
criteria for hospital referral and admission.
Apart from absolute readings, trends and The optimal interval between the acute and
clinical correlations should be taken into the convalescent serum is 10 days. Serial
consideration. A rising hematocrit and (paired) specimens are required to confirm
falling platelet counts is ominous. or refute a diagnosis of acute flavivirus or
dengue infection.
Dengue serology and confirmatory tests
Five basic serological tests are used for New technologies available for the
diagnosis of dengue infection: laboratory diagnosis of dengue infection
haemagglutination-inhibition (HI), include immunohisto-chemistry on
complement fixation (CF), neutralization autopsy tissues and polymerase chain
test (NT), IgM-capture enzyme-linked reaction (PCR) to detect viral RNA in the
immunosorbent assay (Mac-ELISA), and tissue or serum.
Dot Blot Immunoassay. Mac-ELISA
appears to be the most important A number of serologic test kits for anti-
serological test for a rapid diagnostic dengue IgM and IgG antibodies have
technique. However, further become available in the past few years,
standardization is required.6 some producing results within minutes.
Unfortunately most of these tests are not
Laboratory tests for confirmatory well validated. It is important to note that
diagnosis of dengue infection include: these kits should not be used in the clinical
isolation of the virus, setting to guide management of DF/DHF
demonstration of a rising titre of cases because many serum samples taken
specific serum dengue antibodies, and in the first five days after the onset of
demonstration of a specific viral illness will not have detectable IgM
antigen or RNA in the tissue or antibodies. The use of a rapid test alone is
serum. not sufficient to diagnose dengue infection
even if antibodies are detected. A negative
test does not preclude the possibility of
6dengue infection. There are concerns that when it is no longer safe to manage the
reliance on such tests to guide clinical case in an outpatient setting.
management may result in an increase in
case fatality rates.4 Prompt notification even of suspect cases
is important to allow public health
Medications measures to be implemented. The criteria
Avoid the use of NSAIDs in the for suspect dengue fever is as follows:5
management of pain and fever when there
is a possibility of dengue infection as this A suspect case of dengue fever is defined
will increase the likelihood of hemorrhagic as an acute febrile illness with 2 or more
complications. of the following features: headache, eye
pain, myalgia, arthralgia, rash,
Paracetamol is metabolized by the liver haemorrhagic manifestations, leucopenia.
and is hepatotoxic in high doses. As the
liver can be adversely affected in a dengue Hospital referral and admission criteria
infection, the dosage of paracetamol The clinical course of DHF can be
should be kept low. modified by early diagnosis and prompt
correction of plasma loss. Early and
General advice appropriate referral is important. The
Dengue patients that do not need admission criteria recommended by the
hospitalization should be given medical MOH’s committee of experts are as
leave to rest at home and advised to follows: 7
maintain good hydration. 7 As viraemic
patients can serve as reservoirs of infection, Presence of any ONE of the following
patients and household members should be justifies referral to hospital
advised on precautionary measures against • Significant bleeding
mosquito bites including the use of insect • Fall in blood pressure
repellents and mosquito coils.5 • Dehydration and postural hypotension
• A rise in hematocrit ≥ 20% above
Follow-up and discharge consideration baseline
Mild and stable cases with good home • Platelet count < 80,000 cells per cubic
environment and access to follow-up mm
should be monitored closely at home. • Severe vomiting or diarrhea
Patients should be advised to monitor for • Severe abdominal pain
gum bleeding, epistaxis, easy bruising, • Elderly patients with co-morbidities
malena, hemetemesis and menorrhagia. who are unwell
They should also be educated and advised
to seek emergency treatment if they PREVENTIVE MEASURES
develop severe abdominal pain or
symptoms of circulatory failure. Insect repellents
The active ingredients in repellents
Patients should be reviewed at least once a (usually a compound known as DEET)
day. Assessments at such visits should repel but do not kill mosquitoes. Most
include general condition, circulatory repellents are only effective a short
sufficiency, presence of hemorrhagic distance away from the site of application
phenomenon and hydration. Blood (estimated to be about 4 cm) Although
investigations should include total white neck, wrists and ankles are often
cell count, hematocrit and platelet count. mentioned as target areas for application
Patients should be referred to the hospital all exposed skin is at risk. Care must be
if they fulfill the admission criteria or taken to avoid mucous membranes (nose
7and eyes). When applied on the skin, the sunlight. Nevertheless prolonged use is
repellent effect may last from 15 minutes best avoided. The lighted mosquito coil
to 10 hours, depending on a number of can be a fire hazard and precaution must
factors including climate and humidity, the be taken.
formulation of the product, the
concentration of the formulation and the Protective clothing
species of the biting insect. Applying Protective clothing can be effective but
repellents on clothing extends their their practicality is limited in our hot and
duration of effectiveness. humid climate. The thickness of the
material is critical, and no skin should be
Insecticide spraycans left exposed, unless treated with a repellent.
Insecticide spraycans are effective for an Clothing is a good substrate for the
immediate knockdown and killing effect application of repellents for certain
on the mosquitoes in range of the spray. insecticides such as synthetic pyrethroids.
However, there is hardly any residual The effectiveness of the repellent is
effect. Spraying a room with an insecticide extended.
spraycan will help to free it from
mosquitoes soon after the spray. It will Air-conditioning
not keep the room mosquito free. The use Air-conditioning is fairly effective in
of spraycans can be made more effective keeping mosquitoes and other flying
by combining with a mosquito coil or insects out of a room. This is only
mosquito net. Spraying is useful in effective when the room is closed to the
reducing mosquito population and killing surrounding. Mosquitoes that are already
mosquitoes that are harbouring indoors. in the room remain unless they are killed
Killing of mosquitoes that carry the virus off by insecticides.
is better than just repelling it.
RECOMMENDED READING AND
Mosquito coils SOURCES OF INFORMATION
Mosquito coils are actually insecticide
vaporizers, usually with a synthetic Dengue Information Websites
pyrethroid as the active ingredient. Under Singapore
usual conditions, one coil is effective for a • MOH Weekly Infectious Disease
normal bedroom for one night. Air Bulletin at:
currents in well ventilated rooms have a http://www.moh.gov.sg/corp/publicatio
diluting effect on the insecticide. The ns/idbulletin.
coils tend to burn faster and shorten the • Answers to Frequently Asked
period of effectiveness. Some versions Questions for the public:
place the insecticide mat on an electrically http://www.moh.gov.sg/corp/about/faq
heated grid and the insecticide evaporates s/illness.do.
from the substrate. The smoke from coils • Areas with cases of dengue in
deters the mosquitoes from entering the Singapore:
room, while those inside are expelled or http://www.moh.gov.sg/dengue_hotspo
their host finding ability is affected. A ts
significant proportion of them are knocked
down and killed. Studies indicate that the International Health Organisations
allethrin group of chemicals are • World Health Organisation website on
metabolised in mammals rapidly and there Dengue
were no reports of accumulation of these http://www.who.int/topics/dengue/en/
compounds in animal tissues. They are
highly biodegradable and disintegrate in
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• Ministry of the Environment. Dengue 3
Potasman I et al. Emerging Infectious Diseases.
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