Dengue


– Dengue fever is an arbovirus transmitted to humans by the bite of a mosquito (Aedes). Transmission by transfusion of contaminated blood and transplacental transmission to the foetus have also been reported.
– Four different serotypes of dengue have been described. Infection with one serotype provides a lifelong immunity to that specific serotype, but only partial, short-term immunity to other serotypes. There is no specific antiviral treatment.
– Dengue is a mainly urban disease, present in tropical and subtropical regions1 , in particular in Asia, Central and South America and the Caribbean. Outbreaks have been described in Eastern Africa.
– Primary infection may be asymptomatic or present as mild dengue fever. Subsequent infections increase the risk of severe dengue.

Clinical features

After the incubation period (4 to 10 days), the illness occurs in 3 phases:
 Febrile phase: high fever (39 to 40 °C) lasting 2 to 7 days, often accompanied by generalized aches, a maculopapular rash and mild haemorrhagic manifestations.
– Critical phase (between the third and seventh day): decrease in temperature. The majority of patients will have dengue without warning signs and proceed to the recovery phase. Certain patients will develop dengue with warning sign(s) or severe dengue.
– Recovery phase: patient improves, vital signs normalise, gastrointestinal symptoms subside and appetite returns. At times, bradycardia and generalized pruritus.

Symptoms according to severity (adapted from the WHO)

Dengue
without warning signs

Fever + 2 of the following symptoms:
• Nausea, vomiting
• Rash resembling measles
• Generalized aches (headache, retro-orbital pain, myalgias, arthralgias)
• Benign mucocutaneous bleeding (petechiae, positive tourniquet test2 , epistaxis, gingival bleeding)
• Leucopenia

Dengue
with warning signs

Presence of at least one of these symptoms:
• Abdominal pain
• Persistent vomiting
• Fluid accumulation (ascites, pleural effusion)
• Mucosal bleeding
• Hepatomegaly (> 2 cm)
• Agitation or lethargy
• Increasing haematocrit and rapidly dropping platelet count

Severe dengue

• Severe plasma leakage with:
- Fluid accumulation (ascites, pleural effusion) + respiratory distress
- Compensated shock: weak and rapid pulse, hypotension, cold extremities, capillary refill time > 3 seconds
- Decompensated shock: heart rate and blood pressure unrecordable
• Severe mucocutaneous bleeding
• Multiorgan failure e.g.: hepatic or cardiac failure, obtundation, coma

Major differential diagnoses

Malaria, influenza, measles, Chikungunya, mononucleosis, primary HIV-infection, sepsis, meningococcemia, typhoid fever, viral haemorrhagic fever, leptospirosis.

Laboratory

Diagnostic

– Rapid diagnostic test (serum, plasma or whole blood) detects NS1 viral antigen during the febrile phase and IgM and IgG antibodies during the critical and recovery phases.
– This test indicates the likely presence of an infection with dengue virus but the results must be confirmed by molecular techniques (PCR) in a reference laboratory.

Monitoring the haematocrit (Hct) and complete blood count

– The haematocrit (and not the haemoglobin) is the only test that shows haemoconcentration or increased vascular permeability (plasma leakage). The Hct reflects disease evolution and suggests therapeutic response.
– In children and pregnant women and if possible, in all patients, measure a reference Hct (Hct 0) at the first visit (during the febrile phase or before the critical phase).
– Measure baseline Hct on admission before administering fluid boluses (Hct 1) for all patients in Groups B and C then monitor Hct to determine therapy.
– An increase in the Hct with a rapid drop in the platelet count (≤ 100 000/mm3) is a warning sign.
– In case of hemodynamic instability or signs of shock:
• An increased or a persistently high Hct (> 50% in men or an increase relative to the previous Hct in women and children) indicates severe plasma leakage;
• A decrease in Hct (< 40-45% in men, < 35-40% in women and children 1 year and older, < 30-35% in children under 1 year) may indicate a haemorrhage.
– Leukopenia (< 5 000/mm3) is frequent.

Treatment of patients in Group A

Patients with no warning signs, able to drink sufficiently and with a normal urine output.
– Treat as outpatients, bed rest and good hydration.
– Fever: paracetamol PO at the usual doses (see Fever, Chapter 1), maintaining a strict 6 to 8 hour interval between doses. Do not prescribe acetylsalicylic acid, ibuprofen or other AINS drugs.
– Seek medical attention if: no clinical improvement, persistent vomiting, cold extremities, agitation or lethargy, breathing difficulties or absence of urine output.
– If follow-up is impossible or symptoms cannot be monitored at home (patients living far from the health care facility/living alone), hospitalise for observation.

Treatment of patients in Group B

Patients with warning sign(s) or co-morbidities (e.g. diabetes mellitus, hypertension, cardiac or renal failure, sickle cell anaemia) or at risk populations (pregnant women, infants, the elderly, patients with difficulty drinking).

In all cases:
– Hospitalise; place the patient under a mosquito net.
– Measure Hct 1 and baseline platelet count.
– Avoid invasive procedures (nasogastric tube, IM injections) to minimize the risk of bleeding.
– Fever: paracetamol PO as in Group A. In case of hepatitis, administer with caution and decrease the dose (children: 10 mg/kg 3 times daily; adults: 500 mg 3 times daily; maintaining a strict 8-hour interval between doses).

If warning signs or dehydration:
– Place an intravenous line and start hydration with Ringer lactate.
– Monitor the Hct every 4 to 6 hours until the patient is stabilized.
– The volume and rate of Ringer lactate administration is determined by the vital signs: heart rate (HR), blood pressure (BP) and by the evolution of the Hct. See Table 1 – Group B: dengue with warning signs or dehydration.
– Monitor fluid balance: intake (IV and oral) and output (urine).
– Monitor urine output every 4 hours: administer the volume of IV fluids necessary to ensure that the urine output is at least 1 ml/kg/hour in children and 0.5 ml/kg/hour in adults. If unavailable, ensure that the patient is urinating at least every 4 hours.

Table 1 – Group B: dengue with warning signs or dehydration

Measure Hct 1 then
Children and adults:
Ringer lactate
5-7 ml/kg/h for 1-2 h
3-5 ml/kg/h for 2-4 h
2-3 ml/kg/h for 2-4 h or less depending on clinical response

  • Re-evaluate the clinical signs (vital signs, capillary refill time, urine output) hourly and measure Hct 2 then repeat the Hct every 4-6 hours or more if necessary.
  • Adjust the rate of the IV infusion in order to maintain a urine output of 1-2 ml/kg/h in children and 0.5 ml/kg/h in adults.

Hct 2 identical to Htc 1
or minimally increased


Children and adults:
Ringer lactate
2-3 ml/kg/h for 2-4 h

Hct 2 increased relative to Hct 1 and/or tachycardia and/or hypotension (if shock: see Group C)

Children and adults:
Ringer lactate
5-10 ml/kg/h for 1-2 h

Re-evaluate the clinical signs and measure Hct 3.

Htc stable

Children and adults:
Ringer lactate
3-5 ml/kg/h for 2-4 h
2-3 ml/kg/h or less depending on clinical response

Hct increased or vital signs unstable

Children and adults:
Ringer lactate
5-10 ml/kg/h for 1-2 h and re-evaluate as above

  • If no improvement treat as a Group C patient.
  • If improvement (disappearance of the danger signs, improvement of the urine output or PO fluid intake or normalisation of the Hct) gradually reduce the rate of IV fluid administration. Duration of IV fluid administration: 24-48 h.

Treatment of patients in Group C

Patients with severe dengue requiring emergency treatment.

In all cases:

– Hospitalise in intensive care; place the patient under a mosquito net.
– Administer oxygen (O2) continuously:
• to maintain the SpO2 between 94 and 98% if it is ≤ 90%3 or if the patient has cyanosis or respiratory distress;
• if pulse oxymeter is not available: at least 5 litres/minute or to relieve the hypoxia and improve respiration.
– Before first bolus, measure Hct 1, baseline platelets count and blood group, then monitor the Hct every 1 to 4 hours until the patient is stabilized.
– Check for the presence of the shock: rapid and weak pulse, low BP or narrow pulse pressure, cold extremities, capillary refill time > 3 seconds.
– Mark the size of the liver with a pen on admission.
– The volume and rate of Ringer lactate or plasma substitute administration is determined by the vital signs (HR, BP) and by the evolution of the Hct. See Table 2 – Group C: dengue with compensated shock or Table 3 – Group C: dengue with decompensated shock.
– Monitor urine output: same monitoring as in Group B.
– Monitor signs of fluid overload (especially in children):
• Increase in RR ≥ 10/minute or tachypnoea;
• Increase in HR ≥ 20/minute or tachycardia and SpO2 < 90%;
• Rales and/or pulmonary oedema (fine crackles);
• Gallop rhythm on cardiac auscultation;
• Increase in liver size;
• Peripheral oedema (e.g. eyelid oedema).
– In the event of fluid overload, stop the IV infusion if vital signs are stable.
– In the event of respiratory distress with rales, administer furosemide IV (see Heart failure, Chapter 12) if the patient is not in shock.
– Avoid invasive procedures (nasogastric tube, IM injections) to minimize the risk of bleeding.
– Transfuse patients with fresh whole blood4 in case of significant bleeding or if a low Hct does not improve with resuscitation. The post-transfusion Hct should be interpreted with caution.

– When the patient improves, stop the IV infusion to avoid fluid overload.

Table 2 – Group C: dengue with compensated shock
(BP maintained but signs of shock present)

Measure Hct 1 then give Ringer lactate (first bolus)
Children: 10-20 ml/kg in 1 h
Adults: 5-10 ml/kg in 1 h

If improvement
(no signs of shock present)


Reduction of rate:

Children:
Ringer lactate
10 ml/kg/h for 1-2 h
7 ml/kg/h for 2 h
5 ml/kg/h for 4 h
3 ml/kg/h

Adults:
Ringer lactate
5-7 ml/kg/h for 1-2 h
3-5 ml/kg/h for 2-4 h
2-3 ml/kg/h for 2-4 h

If no improvement (signs of shock present): measure Hct 2.

Hct 2 increases or stays elevateda

Children: plasma substitute
10-20 ml/kg in 1 h (second bolus)
10 ml/kg in 1 h
7 ml/kg in 1 h

Adults: Ringer lactate or plasma substitute
10-20 ml/kg in 1 h (second bolus)

Hct 2 decreasesb

Look for severe haemorrhage.

If improvement
(no signs of shock present)

Children:
Ringer lactate according to “Reduction of rate in children

Adults:
Ringer lactate
7-10 ml/kg/h for 1-2 h
Then according to Reduction of rate in adults

If no improvement
(signs of shock present)

Measure Hct 3 and proceed as above from “Measure Hct 2”.

No severe haemorrhage

Children and adults:
plasma substitute
10-20 ml/kg in 1 h
Evaluate need for transfusion if no improvement.

Severe haemorrhage

Transfuse
Children and adults:
fresh whole blood
10-20 ml/kg

Verify presence of signs of shock, of fluid overload and measure Hct, then reduce the rate as in “Reduction of rate” if signs of shock are absent.
  • Reduce the rate when the HR and BP normalise. Always check for signs of fluid overload.
  • Continue for 24-36 h (less if PO hydration is tolerated). Supplemental boluses of crystalloids or colloids may be necessary in the next 24 h. Do not administer IV fluids for more than 48 h.

a  > 50% in men or increased relative to Hct 1 in women and children.
b  < 40-45% in men, < 35-40% in women and children 1 year and older, < 30-35% in children less than 1 year.

Table 3 – Group C: dengue with decompensated shock
(pulse and blood pressure unrecordable)

Measure Hct 1 then Ringer lactate or plasma substitute (if pulse pressure < 10 mmHg or severe hypotension) IV or IO :
Children and adults: 20 ml/kg in 15-30 min (first bolus)

If improvement
(no signs of shock present)

Children:
plasma substitute
10 ml/kg in 1 h
Adults:
Ringer lactate
or plasma substitute
10 ml/kg in 1 h

Reduction of rate:
Ringer lactate
Children:
10 ml/kg in 1 h
7 ml/kg/h for 2 h
5 ml/kg/h for 4 h
3 ml/kg/h
Adults:
5-7 ml/kg/h for 1-2 h
3-5 ml/kg/h for 2-4 h
2-3 ml/kg/h for 2-4 h

If no improvement (signs of shock present)

Compare Hct 1 (obtained before the first bolus) to Hct 0a (obtained during the febrile phase or before the critical phase).

Hct 1 increases or stays elevated relative to Hct 0

Children and adults:
plasma substitute 10-20 ml/kg in 30-60 min (second bolus)
Verify the presence of signs of shock or of fluid overload.

Hct 1 decreasesb relative to Hct 0

Verify the vital signs and look for signs of severe haemorrhage.

If improvement

Children and adults:
plasma substitute
7-10 ml/kg/h for 1-2 h

Then Children and adults:
Ringer lactate as in Reduction of rate

If no improvement: measure Hct 2

No severe haemorrhage

Children and adults:
plasma substitute
10-20 ml/kg in 30-60 min (second bolus)
Transfuse if no improvement.

Severe haemorrhage

Transfuse
Children and adults:
fresh whole blood
10-15 ml/kg

If Hct 2 < Hct 1:
Severe haemorrhage

Transfuse
Children and adults:
fresh whole blood
10-15 ml/kg

If Hct 2 ≥ Hct 1:
No severe haemorrhage

Children and adults:
plasma substitute (third bolus)
10-20 ml/kg in 30-60 min
7-10 ml/kg/h for 1-2 h

If improvement

Children and adults:
Ringer lactate as in Reduction of rate


If no improvement

Measure Hct 3 and proceed as above from “Measure Hct 2”.

Verify the presence of signs of shock or of fluid overload and measure Hct.
Reduce the IV fluid rate when HR and BP normalise; continue for 24-48 h (or less if PO hydration tolerated). Supplemental boluses of crystalloids or colloids may be necessary in the next 24 h. Do not administer IV fluids for more than 48 h.

a  If not available, compare to population norms of haematocrit according to age. If these are not know use the following norms as a reference: < 45% in men, < 40% in women and children 1 year or older, < 35% in children less than 1 year.
b  < 40-45% in men, < 35-40% in women and in children 1 year and older, < 30-35% in children less than 1 year.

Prevention

Individual protection: long sleeves and trousers, repellents, mosquito net (Aedes bites during the day).



Footnotes
Ref Notes
1 For more information: http://gamapserver.who.int/mapLibrary/Files/Maps/Global_DengueTransmission_ITHRiskMap.png?ua=1
2 Tourniquet test: inflate a blood pressure cuff on the upper arm to a point midway between the systolic and diastolic pressure for 5 min. The test is positive when 20 or more petechiae per 2.5 cm square are observed.
3

If possible it is better to treat all patients with a SpO2 < 95% with oxygen.

4 Fresh whole blood: that has never been refrigerated, that has never kept at a temperature below 16 °C and collected from the donor for less than 6 hours.