Dengue Fever

Introduction

What is Dengue Fever?

Dengue fever is a globally important arboviral infection and by far the most devastating of all the recognized arthropod transmitted virus diseases.^1,2 The word” dengue” is derived from the Swahili phrase “Ka-denga pepo”, meaning “cramp-like seizure”.³ Dengue fever was reported for the first time in India in 1956 from Vellore town of Tamilnadu.⁸

Who gets Dengue Fever?

The geographical areas in which dengue transmission occurs have expanded, and they are now circulating in Asia, Africa, and the Americas.⁴ The infection is now endemic in more than 100 countries particularly the South East region, Western Pacific region, Americas.¹

What causes Dengue Fever?

VECTOR: The primary vector for the spread of infection is Aedes aegypti, a highly domesticated day-biting mosquito, with Aedes albopictus also responsible for transmission. They are Asian in origin, but also found in Africa, Europe, US.¹ It breeds in clean stagnant water in containers that collect rainwater. It bites several people in a short period of one blood meal.⁸ Mosquito vector becomes infected when they feed on humans during the usual 5 day period of viremia. The virus has an extrinsic incubation period of 10 days in the salivary gland, which is most rapid at high ambient temperatures.⁴ The temperature rise of 1-2 degrees Celsius could increase the vulnerable population by 700 million per annum.⁵ The mosquito that bites after the extrinsic incubation period results in infection.⁴ Peak dengue transmission occurs about 6-8 weeks after peak rainfall.⁸

CAUSATIVE AGENT - DENGUE VIRUS: Dengue virus belongs to the genus flavivirus within the Flaviviridae family.⁴ The viral positive single-strand RNA genome encodes 3 structural proteins the Capsid (C), membrane (M), and envelope (E) glycoproteins, and 7 non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5).⁴ The amino acid sequences of the E proteins determine the antibody neutralizing activity, that classifies DENV into 4 serotypes- DENV-1, DENV-2, DENV-3, DENV-4.⁵ Humans are the main reservoir of the dengue virus.⁸

HOST: Host factors that increase the risk of severe dengue disease include female sex, several HLA class 1 alleles, AB blood group, single nucleotide polymorphism in the TNF gene. Host factors that reduce the risk of severe dengue during the second infection include race, second or third-degree malnutrition, polymorphisms in the FcY receptor, and vitamin D receptor genes.⁴ The exponential increase in emergence and re-emergence of dengue fever and DHF is due to a rise in population, unplanned urbanization, and air travel.⁵

Pathogenesis

Pathogenesis is linked to the host immune response, which is triggered by infection with the virus. Primary infection is usually benign but secondary infection with different serotypes cause severe infection.^1,5 Antigen-presenting dendritic cells, the humoral immune response, and the cell-mediated immune response are involved in pathogenesis. The proliferation of memory T cells and production of proinflammatory cytokines (Cytokine Tsunami) leads to dysfunction of the luminal surface of the vascular endothelium which has a layer of glycocalyx which results in plasma leakage.^1,5 There is also abundant replication of DENV’s in liver parenchymal cells, in macrophages, in lymph nodes, liver and spleen, and peripheral blood monocytes. Antibody-dependent enhancement (ADE) occurs when mononuclear phagocytes are infected through their Fc receptors by immune complexes that form between DENV’s and non-neutralizing antibodies. These non-neutralizing antibodies result from previous heterotypic dengue infections or from low concentrations of dengue antibodies of maternal origin in infant sera. Hence ADE theory can cause DHF in both primary infection in infants and secondary infection at any age.^4,5

Physical Examination

• Diffuse skin flushing of the face, neck, and chest develops early in the infection. This evolves into a maculopapular or rubelliform rash of the whole body on day 3 or 4 of fever, which is associated with blanching when pressed.¹

• Hemorrhagic signs-Minor hemorrhage includes petechiae, purpura, positive tourniquet test (BP cuff is inflated to a point midway between systolic and diastolic blood pressures for 5 minutes. The test is positive if >10 petechiae per square inch or per 2.5 square cm appear on the forearm)¹, conjunctival hemorrhage.

• Major hemorrhage includes epistaxis, gingival bleeding, and hematemesis. Malena, metromenorrhagia, bleeding from venepuncture site. These signs can occur either in DF or DHF.^1,5
• Hepatomegaly

• Plasma leakage-Ascites, postural dizziness, or pleural effusion leading to respiratory distress. These are seen in DHF.^1,5

• Circulatory collapse-cold clammy skin, rapid and weak pulse with narrowing of pulse pressure to <20 mm Hg with decreased diastolic pressure, a postural drop of blood pressure >20 mmHg, capillary refill time greater than 3 seconds, reduced urine output, indicates the presence of shock and supports the diagnosis of dengue shock syndrome.^1,5

  Of these manifestations bleeding and hepatomegaly are highly correlated with the progression of DF into severe dengue disease (SDD).⁶

Phases Of Infection

• The incubation period is 3-14 days (average 7 days).

• Febrile phase is characterized by a sudden high-grade fever and dehydration which lasts for 2-7 days.

• Critical phase is characterized by plasma leakage, bleeding, shock, and organ impairment and lasts for 24-48 hours. It starts around the time of defervescence, typically days 3 to 7 of infection.

• Spontaneous recovery phase is characterized by a stoppage of plasma leak and plasma returns to circulation. The patient starts passing copious amounts of dilute urine, develop bounding pulses, wide pulse pressure, and a rise in blood pressure. Appetite improves and the patient feels better.¹

Warning Signs For Severe Dengue

• Abdominal pain or tenderness

• Persistent vomiting

• Clinical fluid accumulation

• Mucosal bleed

• Lethargy, restlessness

• Liver enlargement >2 cm.

• Laboratory: Increase in hematocrit concurrent with rapid increase in platelet count

Criteria For Severe Dengue

1. Severe plasma leakage
• Shock (DSS)

• Fluid accumulation with respiratory distress
2. Severe bleeding
3. Severe organ involvement
• Liver: ALT >1000 IU/L

• CNS: Impaired consciousness

• Involvement of Heart and other organs

Dengue Fever - History

• High grade fever with spikes of 39.4-40.5 degree Celsius. It may be biphasic and last for 5-7 days.

• Aches particularly backaches, myalgia, arthralgia, bone pain, headache, retro-orbital pain in adolescents and older children

• Gastrointestinal symptoms like anorexia, nausea or vomiting, epigastric discomfort or pain.

• Lethargy, restlessness, collapse or dizziness may be present.

• Upper respiratory tract symptoms-sore throat, cough are rare.^1,5

Supportive Lab Investigations

CBC:

• Leucopenia is common initially, of which neutrophils usually predominate. Towards the end of the febrile phase, there is a drop in total white cells and neutrophils. A relative lymphocytosis with more than 15% atypical lymphocytes is observed at the end of the febrile phase and at the early stage of shock. The absence of leucopenia and a relatively low percentage of typical lymphocytes predict severe dengue illness.^1,8

• Leucopenia in combination with a positive tourniquet test in a dengue-endemic area has a positive predictive value of 70-80%.¹

• Thrombocytopenia below 1 lakh/cumm is found between the third and eighth days of illness.⁸ Parallel drop in platelets and progressive leucopenia precedes plasma leakage.⁵ By the ninth day platelets increase and recovers within 2 weeks.⁵

• Hematocrit rises by 10% due to dehydration. If it rises by 20% or more it is objective evidence of increased vascular permeability and leakage of plasma.^1,8

LIVER FUNCTION TESTS:

• Mild elevation in transaminase levels may be seen

• Low albumin is a sign of hemoconcentration^1,8

COAGULATION STUDIES:

• Partial thromboplastin time and prothrombin time (PT) is prolonged in about one-half and one-third of DHF cases respectively. Delayed PT is a risk factor for DSS.

• Low fibrinogen and elevated fibrin degradation product levels are signs of disseminated intravascular coagulation.

• In severe cases with marked liver dysfunction, the reduction is observed in vitamin dependent prothrombin family such as factors V, VII, IX and X.^1,8

METABOLIC TESTS:

• Hyponatremia, metabolic acidosis and elevated BUN are observed in patients with shock.⁸

Confirmatory Laboratory Investigations

Table 1.Advantages and disadvantages of confirmatory laboratory tests for dengue fever (1)

Table 2: Interpretation of NS 1 and dengue serology (8)

Laboratory criteria for the diagnosis of dengue hemorrhagic fever or dengue shock syndrome

• Rapidly developing, severe thrombocytopenia

• Decreased total white cell count and neutrophils and changing neutrophil to lymphocyte ratio

• Increased hematocrit (20% increase from baseline is objective evidence of plasma leakage)

• Hypoalbuminaemia (serum albumin <35 g/L suggests plasma leakage)

• Increased liver function test results(aspartate aminotransferases:alanine aminotransferase >2)

Imaging

• Chest radiograph- A lateral decubitus chest radiograph of the right side of the chest detects undetectable pleural effusion in the early phase of plasma leakage. Bilateral pleural effusions are common in inpatient with DSS.^1,7,8

• Ultrasonography is useful to detect the presence of ascites, pleural effusion, and gallbladder wall edema, which is common during the critical phase and correlates with disease severity. Gall bladder wall edema precedes ascites and effusions hence helpful as an early predictor of outcome. But gallbladder thickness may be increased in other infections and in postprandial states.^7,1

Management

Proper dengue management has the following principles,

• Suspicion of disease

• Assessment and management of early febrile phase

• Identifying patients with early warning signs

• Recognising early critical phase and initiating timely fluid therapy

• Recognising and managing severe dengue shock, massive bleeding and severe organ impairment⁵

The practical treatment plan is produced by World Health Organization (WHO) and is based on the severity of infection.

Group A: These are patients who may be sent home. These patients are able to tolerate adequate volumes of oral fluids, pass urine at least once every six hours, and do not have any of the warning signs (particularly when the fever subsides). Patients are advised to frequent oral fluids. Give paracetamol (10 mg/kg/dose) for high fever, not more than 3-4 times in 24 hours in children. Do not give aspirin, ibuprofen, or other non-steroidal anti-inflammatory agents (NSAIDs) or intramuscular injections, as these aggravate gastritis or bleeding. Instruct caregivers that the patient should be brought to the hospital immediately if any of the warning signs appear. Monitor complete blood counts.

Group B: These are patients who should be admitted for in-hospital management for close observation as they approach the critical phase. These include patients with warning signs, those with co-existing conditions that may make dengue or its management more complicated (such as pregnancy, infancy, old age, obesity, diabetes mellitus, hypertension, heart failure, renal failure, chronic hemolytic diseases such as sickle-cell disease and autoimmune diseases). If the patient has dengue with warning signs or signs of dehydration, judicious volume replacement by intravenous fluid therapy is recommended. Give only isotonic solutions such as 0.9% saline, Ringer's lactate, or Hartmann's solution. Start with 5-7 ml/kg/hour for 1-2 hours, then reduce to 3-5 ml/kg/hour for 2-4 hours, and then reduce to 2-3 ml/kg/hour or less according to the clinical response. Give the minimum intravenous fluid volume required to maintain good perfusion and urine output of about 0.5 ml/kg/hour. Intravenous fluids are usually needed for only 24-48 hours. Parameters that should be monitored include vital signs and peripheral perfusion, urine output, hematocrit, blood glucose, and other organ functions as indicated

Group C: These are patients with severe dengue. Plasma losses should be replaced immediately and rapidly with an isotonic crystalloid solution: in the case of hypotensive shock, a colloid solution is preferred. Larger volumes of fluids (e.g. 10-20 ml/kg boluses) are administered for a limited period of time under close supervision, to evaluate the patient’s response and to avoid the development of pulmonary edema. Then reassess the patient’s condition (vital signs, capillary refill time, hematocrit, urine output). If the adult patient’s condition improves, intravenous fluids should be gradually reduced to 5-7 ml/kg/hour for 1-2 hours; then 3-5 ml/kg/hour for 2-4 hours, and finally 2-3 ml/kg/hour which can be maintained up to 24-48 hours. The total duration of intravenous fluid therapy should not exceed 48 hours.

Convalescence And Discharge

Convalescence is recognized by improvement in the clinical wellbeing and appetite of patients. The patient has diuresis, hypokalemia. The patient also develops a rash and generalized pruritis.¹ Hematocrit decreases with stable hemodynamic status which indicates hemodilution and suggestive of stoppage of IV fluids.⁵ Once wellbeing is achieved and the patient remains afebrile for 48 hours with an increased platelet count and stable hematocrit, they can be discharged.¹

Adjunctive Therapies

Platelet transfusions are only required in the presence of active bleeding. The clinical value of fresh frozen plasma, corticosteroids, intravenous immunoglobulin, and antibodies is controversial and more evidence is required before they can be recommended.¹

Patient Instructions

Avoid strenuous activities during convalescence as LFT takes 3 weeks to return to normal.¹

Disease Notification

In dengue-endemic regions suspected, probable, and confirmed cases of dengue fever should be reported to relevant authorities as soon as possible so measures are instituted to prevent transmission.¹

Disease Control Strategies

Vactor Control of Larvae and Adult Mosquito

Aedes aegypti are more effectively susceptible to temephos, followed by fenthion, malathion, and DDT. Peridomestic thermal fogging reduced the resting and biting for the 3 days after treatment, whereas indoor fogging suppressed the adult population for 5 days.³ Plant-based repellents against mosquito-borne diseases i.e. flavonoid compounds derived from Poncirus trifoliate, larvicidal, and ovicidal activities of chloroform leaf extract of Ecliptic alba have shown effective for controlling Aedes aegypti mosquitoes.⁸ Elimination of artificial containers such as plastic cups, used tires, broken bottles, flower pots, other water traps reduce mosquito breeding grounds.² An alternative approach involves infecting Aedes aegypti with the bacterium Wolbachia which reduces the life span of adult mosquito by 50%.

Insect Repellenets

Use of insect repellents, mosquito traps, and nets in homes is moderately effective in reducing the number of bites.² Wear protective clothing (long pants and long-sleeved shirts). Use insect repellent with DEET (N, N diethyl-meta toluamide). The repellent is available in varying strengths up to 100%. The American Academy of Paediatrics (AAP) and other experts suggest that it is safe to use a repellent that contains 10% to 30% DEET on children older than age 2 months. Spray clothing with an insect repellent containing permethrin or DEET, because mosquitoes may bite through thin clothing. (Be aware that DEET can damage plastic items, such as watch crystals or eyeglass frames, and some synthetic fabrics.) Sleep under bed nets (mosquito netting) sprayed with or soaked in an insecticide such as permethrin or deltamethrin. Use flying-insect spray indoors around sleeping areas.¹¹

Dengue Virus Vaccine

The ideal dengue vaccine should be free of important reactogenicity, induce lifelong protection against infection with any one of 4 DENV serotypes and be affordable.⁴ The first dengue vaccine Dengavaxia (CYD-TDV) by Sanofi Pasteur was first registered in Mexico in December 2015. It is a live recombinant tetravalent dengue vaccine that has been evaluated as a 3 dose series on a 0/6/12 month schedule in phase III clinical studies. It is registered for use in Individuals 9-45 years of age living in endemic areas.⁹

Complications

• Major bleed-GI bleed and vaginal hemorrhages due to poorly managed DSS culminating into multi-organ dysfunction and consequential DIVC. 10 ml/kg of fresh PRBC or 20 ml/kg of fresh whole blood can be transfused. (stored blood loses 2,3 di phosphoglycerate which depletes the oxygen-carrying capacity of hemoglobin resulting in functional tissue hypoxia).

Respiratory distress-Acute pulmonary edema, severe metabolic acidosis from severe shock, ARDS and polyserositis (severe ascites and pleural effusion)due to fluid overload cause respiratory distress. Oxygen supplementation and furosemide 0.1-0.5 mg/kg/dose IV once or twice daily in a fluid overloaded patient with respiratory distress helps.
Dyselectrolytemia, blood glucose disturbances-Hyponatremia, hypokalemia, hyperkalemia, serum calcium imbalances, and metabolic acidosis are suspected due to incorrect use of hypotonic solutions, diarrhea, and vomiting. Both hypo and hyperglycemia can occur.
Organ impairments- Hepatitis, encephalopathy, encephalitis, and cardiac abnormalities can occur.⁵