DENGUE HEMORRHAGIC FEVER

Introduction:

Dengue fever is an acute febrile infectious disease, caused by all four serotypes (1, 2, 3 or 4) of a
virus from genus Flavivirus, called dengue virus. It’s the most prevalent flavivirus infection of
humans, with a worldwide distribution in the tropics and warm areas of the temperate zone
corresponding to that of the principal vector, Aedes aegypti. When simultaneous or sequential
introduction of two or more serotypes occurs in the same area, there may be an increased number
of cases with worse clinical presentation (dengue hemorrhagic fever). The term ‘hemorrhagic’ is
imprecise, because what characterizes this form of the disease is not the presence of hemorrhagic
manifestations, but the abrupt increase of capillary permeability, with diffuse capillary leakage of
plasma, hemoconcentration and, in some cases, with non-hemorrhagic hypovolemic shock
(dengue shock syndrome).

Epidemiology:

The highest incidence of dengue is in southeast Asia, India and the American tropics, where A.
aegypti can be found. In the 1980s, dengue emerged in explosive epidemics in Rio de Janeiro
(1986 - serotype 1 and 1990 - serotype 2 was isolated in Niterói city), São Paulo and in many
other towns and cities in Brazil. In areas such as southeast of Asia, where all four dengue virus
types are hyperendemic, children are almost exclusively affected, and seroprevalence approaches
100% by young adulthood.

Transmission occurs by the bite of Aedes aegypti female mosquitoes - the same vector of urban
yellow fever - a day-active species with low fly-autonomy that is abundant in and around human
habitations. In Brazil and other countries Aedes albopictus may also be responsible for
transmission. Viremic humans (till the fifth day of disease) serve as the source of virus for
mosquito infection; there is not person-to-person transmission. Movement of viremic humans
provides the principal means of spread, and rapid air travel is a factor in most recent epidemic
emergences.

Although homotypic immunity is complete and lifelong, cross-protection between virus types is
incomplete and transient. As mentioned before, there is a strict association between reinfection
by another serotype and the occurrence of dengue hemorrhagic fever (DHF), due to
immunopathologic processes, such as immune enhancement and immune clearance (see
bibliography). Outbreaks usually occur in summer, when ambiental conditions are ideal for
vectors’ proliferation.

Clinical Manifestations:

Incubation period: 3 - 6 days; some cases may reach 15 days.

Dengue Hemorrhagic Fever (DHF):

The early phase of illness is indistinguishable from dengue fever. After 2 - 5 days, however
(defervescence period), a few cases in the first infection, in contrast with a significant number of
cases after reinfection by another serotype may present with thrombocytopenia (< 100.000
/mm3) and hemoconcetration, the first usually preceding the second. Hemorrhagic
manifestations may or may not occur; the spleen is not palpable, but hepatic enlargement and
tenderness is a sign of bad prognosis. Other manifestations include pleural effusion and
hypoalbuminemia, encephalopathy with normal cerebrospinal fluid.

Diffuse capillary leakage of plasma is responsible for the hemoconcentration. In the presence of
hemoconcentration and thrombocytopenia, the patient is considered to be seized by dengue
hemorrhagic fever and classified according to the following World Health Organization
classification:

 Grade I - thrombocytopenia + hemoconcentration. Absence of spontaneous bleeding.

 Grade II - thrombocytopenia + hemoconcentration. Presence of spontaneous bleeding.
 Grade III - thrombocytopenia + hemoconcentration. Hemodynamic instability: filiform
pulse, narrowing of the pulse pressure (< 20 mmHg), cold extremities, mental
conffusion. 
 Grade IV - thrombocytopenia + hemoconcentration. Declared shock, patient pulseless
and with arterial blood pressure = 0 mmHg (dengue shock syndrome - DSS).

The case-fatality of DHF/DSS is 10% or higher if untreated. With supportive treatment, fewer
than 1% of such cases succumb. Recovery is rapid and without sequelae.

Diagnosis:

Although the etiologic diagnosis of dengue is extremely important and desirable in terms of
Health Public Care, it’s absolutely unnecessary for the early institution of supportive therapy.
Dengue is always a diagnosis of exclusion, and other diseases with the same initial clinical
presentation must be suspected. In order to help the clinician in the detection of severe forms of
dengue (DHF/DSS), even when the definitive diagnosis has not been made yet, there are three
essential laboratory tests that may help in the evaluation of the real clinical conditions of the
patient and its early supportive management: total white blood cells count, total platelets count
and micro-hematocrit.

Laboratory Findings:

 Total White Blood Cells Count: In case of dengue, this test will reveal leukopenia. The
presence of leukocytosis and neutrophilia excludes the possibility of dengue and bacterial
infections (leptospirosis, meningoencephalitis, septicemy, pielonephritis etc.) must be
considered.
 Thrombocytopenia (< 100.000 /mm3): Total platelets count must be obtained in every
patient with symptoms suggestive of dengue for three or more days of presentation.
Leptospirosis, measles, rubella, meningococcemia and septicemy may also course with
thrombocytopenia.
  Hematocrit (micro-hematocrit): According to the definition of DHF, it’s necessary the
presence of hemoconcentration (hematocrit elevated by > 20%); when it’s not possible to
know the previous value of hematocrit, we must regard as significantly elevated the
results > 45%.

Etiologic Confirmation:

It can be obtained by isolating infectious virus, demonstrating viral antigen by immunoassay, or

viral genome by PCR in serum or blood.

Serologic diagnosis is achieved by IgM antibody-capture by enzyme-linked immunosorbent

assay (MAC - ELISA) in two blood specimen taken in a period of 14 days from each other. The
first specimen, taken till the seventh day of the disease, can also be useful for virus isolation by
inoculation of A. albopictus cells or adults mosquitoes, with specific indentification of virus by
immunofluorescence tests employing monoclonal antibody reagents.

Postmortem diagnosis is made by virus isolation or by demonstration of viral antigen (direct

immunofluorescence) from two-specimen visceral fragments (liver, spleen, linfonodes, thymus).

Treatment:

No specific treatment of dengue is available. Early institution of supportive treatment

(fluids replacement and correction of electrolyte imbalances) is the key to
management of patients with dengue in all its forms, since high fever, anorexia,
vomiting and capillary leakage result in some degree of dehydration.

A. Criteria For Home Observation:

 All cases of dengue fever with no need of intravascular fluids replacement;

 Patients regarded as Grade I capable of receiving oral fluids replacement

therapy (OFRT);

 Patients regarded as Grade II capable of receiving OFRT and without

important bleedings.

B. Criteria For Short-Duration Admission In Hospital (12 - 24 hours):

 All cases of dengue fever that need intravascular fluids replacement;

 Patients regarded as Grade I or II with hepatic tenderness;

 All patients regarded as Grade III.

C. Criteria For Long-Duration Admission In Hospital (> 24 hours):

 Patients with no response to fluids replacement therapy after short-duration

admission;

 Patients regarded as Grade I or II with predisposing factors to develop severe

forms of presentation (asthma, allergies, diabetes mellitus, chronic obstructive
pulmonary diseases)

 Patients regarded as Grade II or III with important bleedings;

 All patients regarded as Grade IV.

Intensive monitoring of vital signs and markers of hemoconcentration, replacement of

intravascular volume with lactated Ringer’s solution or isotonic saline, correction of
metabolic acidosis, and O2 therapy is life-saving in patients with DSS. Once the
patient is stabilized and capillary leakage stops and re-absorption of extravasated fluid
begins, care must be taken not to induce pulmonary edema with continued intravenous
fluid administration.

Prevention:

 In areas infested with A. aegypti, patients should be safeguarded from mosquito

bite;

 Combat against the urban vectors (insecticides, avoid water storages inside and
around houses).

 There’s no vaccine available at the moment, although experimental live, attenuated

vaccines developed in Thailand against all four serotypes have been tested clinically;
various approaches to genetically engineered vaccines are also being explored.

References:
 http://nurses.definitelyfilipino.com/index.php/2010/08/all-about-dengue-hemorrhagic-fever/
 http://hubpages.com/hub/Dengue_Hemorrhagic_Fever

Article: Imported Dengue Hemorrhagic Fever, Europe

María Jesús Pinazo (http://www.cdc.gov/eid/content/14/8/1329.htm)

 Dengue infection is an endemic and epidemic urban disease, transmitted by infectedAedes mosquitoes.

Its incidence is increasing in tropical and subtropical areas because of 1) introduction of the virus into
areas where it was not previously endemic, and 2) the spread of the 4 serotypes and the vector in disease-
endemic areas. Infection with 1 serotype provides lifelong homologous immunity only for that serotype,
and after a few months, the presence of non-neutralizing antibodies increases the risk for progression to
dengue hemorrhagic fever (DHF) or dengue shock syndrome when the patient is infected by any of the
other 3 serotypes. We report an imported case with severe clinical manifestations that fulfills DHF
criteria.

A 33-year-old Spanish woman who had worked in Anantapur, India, for 180 days, returned to Spain on
August 1, 2007; on August 3, she traveled to Dubrovnik, Croatia, on holiday. She also had visited
Thailand 45 days before August 1 and Brazil 2 years ago. Two months previously, she experienced a 3-
day episode of fever that spontaneously resolved but without laboratory evidence of dengue. On August
6, she exhibited a high fever, chills, headache, arthralgia, and myalgia, with hypotension and was
admitted to the hospital. Three days later, a confluent maculopapular rash developed. Dubrovnik hospital
laboratory values were hemoglobin (Hb) 143 g/L, packed cell volume (PCV) 41.6%, mean corpuscular
volume (MCV) 84.6 fL, platelet count 97 × 10 9/L, leukocyte count 1.96 × 109/L, aspartate
aminotransferase (AST) 45 U/L, alanine aminotransferase (ALT) 31 U/L, AP 73 U/L, and lactate
dehydrogenase (LDH) 198 U/L. On the fifth day of illness, platelet count was 50 × 10 9/L. Because viral
hemorrhagic fever was suspected, the patient was referred to a specialized hospital in Zagreb. Chest
radiograph and abdominal ultrasound scan showed bilateral pleural and peritoneal effusions.

The patient was treated with fluid and plasma replacement, antipyretics, and ceftriaxone plus doxycycline
to counteract bacterial and other possible tick-borne infections. She was placed under strict isolation
measures while awaiting final diagnosis. The patient was transferred to Barcelona (Spain) University
Hospital on August 14; on the basis of her clinical symptoms, hemorragic fever was suspected. She
exhibited headache, arthralgia, and myalgia. The fever subsided 9 days after the onset of symptoms.
Clinical examination showed a maculopapular rash involving the face, thorax, limbs, and palms and soles,
with diffuse petechiae and bruising. Barcelona University Hospital laboratory values were Hb 105 g/L,
PCV 32%, MCV 86, prothrombin time 12.4 s, AST 347 U/L, ALT 322 U/L, gamma-glutamyl transferase
114 U/L, alkaline phosphatase 194 U/L, LDH 544 U/L, bilirubin 0.5 mg/dL, and C-reactive protein level
6.93 mg/dL. Platelet count and renal function were within normal limits. Urine, blood, and stool cultures
were all negative for bacterial infections.

Serologic tests on day 3 and day 11 after the onset of symptoms were not reactive for Crimea-Congo
hemorrhagic fever (CCHF), chikungunya, yellow fever, Hantaan, Puumala, and Dobrava viruses; HIV 1
and 2; parvovirus B19; cytomegalovirus; Epstein-Barr virus; or rickettsial diseases. Immunoglobulin (Ig)
M tests on day 3 for all 4 dengue virus serotypes were negative. Positive IgG were 1:320 (type 1) and
1:100 (type 3 and 4). A second sample on day 11 showed all 4 IgG serotypes >1:10,000, and IgM
>1:10,000 for serotypes 1, 2, and 4. Results of real-time PCR for CCHF were negative but reverse
transcription–PCR multiplex for dengue virus was positive for dengue type 1 virus. The patient recovered
and was monitored for 2 months.

Since 1977, 15 cases of imported DHF have been reported in Europe. The 4 World Health Organization
(WHO) criteria for DHF diagnosis are 1) fever related to the current process, 2) hemorrhagic
manifestations, 3) low levels of platelets (<100 × 10 9/L) and 4) increased capillary permeability. Our
patient fulfilled all 4 criteria. Few cases of reported DHF fulfill criterion 3 due to the short duration of
severe thrombocytopenia in mild clinical forms. Increased vascular permeability was shown in our patient
by the peritoneal and bilateral pleural effusions.

The probability of diagnosing dengue fever in Europe increases with travel to dengue-endemic areas, in
view of the increase of DHF numbers (2006–2007) and several outbreaks around the world, even during
the nondengue season. Frequent travelers are more at risk for DHF. In a recent European publication,
17% of patients with imported dengue fever exhibited a secondary immune response, thus having a higher
risk of developing DHF in the future. Serologic tests confirm dengue infection only if a 4-fold increase in
titers in consecutive serum samples occurs, as in our case. Dengue virus infection should therefore be
considered in the differential diagnosis of fever in returning travelers. DHF diagnosis, although unusual,
could become more frequent in the future.