Dengue Disease Background

Introduction 

Dengue infection is caused by the dengue virus that belongs to the family Flaviviridae. It is generally self-limiting and rarely fatal.

Epidemiology 

Globally, the estimated dengue infections climb up to 390 million per year, with 96 million symptomatic individuals, and 70% of the burden coming from Asia. An eight-fold increase has been reported to the World Health Organization (WHO) in the past two decades. Data on dengue cases decreased in 2020 to 2021 but was inconclusive due to the Coronavirus disease 2019 (COVID-19) pandemic.  

Dengue infection remains to be endemic in Southeast Asia and the Western Pacific regions. According to the WHO, reported cases increased by 46% and mortality decreased by 2% from 2015 to 2019 in Southeast Asia.  

India, Indonesia, Myanmar, Sri Lanka, and Thailand are among the most highly endemic countries worldwide. In India, dengue infection is endemic in almost all of its regions and major outbreaks have become common in the past decades. In 2015, 15,867 cases were reported in Delhi alone, recording one of the country’s worst outbreaks, totaling 99,913 cases nationwide. Reported cases were ranging between 39,419 to 188,401 from 2016 to 2021.  Based on a study employing the National Disease Surveillance Registry in Indonesia, the incidence rate of dengue infection was 80 per 100,000 person-years in 2016. In 2017, 59,047 cases including 444 deaths and an incidence rate of 22.6 per 100,000 person-years were reported. In Myanmar, the highest number of cases reported was in 2015 tallying 42,913 cases, including 140 fatalities. In Thailand, a review reported 20,000 to 140,000 dengue infection cases from 2000 to 2011.  

The incidence of dengue cases in Malaysia is on an upward trend tallying 181 cases per 100,000 population in 2007 and 361 cases per 100,000 population in 2014. Recently, a total of 43,619 cases were reported in 2023, an increase of 27,475 cases from 2022 in the same period. In the Philippines, 121,580 cases were reported in 2014. Recently, a total of 39,947 cases were reported as of April 2023, which was 43% higher than the previous year. In Singapore, 35,315 cases were reported in 2020, and >12,000 cases have been reported as of June 2022. Recently, only 3,056 cases had been reported as of April 2023, which was a 65% decline from the report in 2022 of the same period. In Vietnam, a total of 31,731 cases were reported as of May 2023, an increase of 18.6% as compared to the report in 2022 of the same period.  

An increase of approximately 300 cases compared to the same period in 2021 has been noted by the National Dengue Control Programme (NDCP) of Cambodia, with >1,200 confirmed cases reported within the first 5 months of 2022. A total of 2,411 cases were recently reported in 2023 by the National Dengue Surveillance System in the country.  

Dengue remains to be non-endemic in China. A study based on the country’s national surveillance data stated that a total of 69,321 cases and 11 deaths were reported from 1990 to 2014. Another study reported that from 2005 to 2020, there were 81,653 indigenous cases, 12,701 imported cases, and 13 deaths from dengue. In Hong Kong, a total of 483 cases were reported from 2001 to June 2011, the majority of which were imported from nearby countries. Recently, there were only 12 cases of dengue and no reported deaths in China from January to February of 2023.  

The reported mortality rates from 2000 to 2015 increased from 960 to 4032, with a decline in the total cases from 2020 to 2021. 

Pathophysiology 

The extrinsic (within mosquito vector) incubation period of dengue is 8-10 days, while the intrinsic (within human host) incubation period is 3-14 days (average of 4-7 days). After 4-10 days of the incubation period, illness begins immediately.

The transmission to humans is usually through the bite of an infected Aedes mosquito, primarily by the female Aedes aegypti, a tropical and subtropical species. Other outbreaks were secondary to Aedes albopictus, Aedes polynesiensis, and Aedes scutellaris. Humans are the main host of the virus. 

There are four serotypes of dengue which include DENV-1, DENV-2, DENV-3, and DENV-4. Each serotype provides a specific lifetime protective immunity against reinfection of the same serotype, but only temporary (within 2-3 months of the primary infection) and partial protection against the other serotypes. The fifth serotype, DENV-5, is a new variant that follows the sylvatic cycle (transmission of dengue virus to non-human primates) while the other 4 serotypes are transmitted between humans. 

Risk Factors 

Risk Factors for Severe Dengue 

The following are the risk factors for severe dengue:

• Abdominal pain
• Bleeding tendencies
• Hepatomegaly
• >22% hemoconcentration from baseline
• Lethargy
• Thrombocytopenia of <100,000/μL
• Other risk factors in children include:
  • Demographic: Age >5 years old, female sex, obesity
  • Epidemiology: Infection with DENV-2, secondary infection with DENV
  • Clinical signs: Systolic blood pressure of <90 mmHg, pulse pressure of <20 mmHg
  • Laboratory: Hemoglobin of <9 g/dL, white blood cell (WBC) count of >5000/μL, prolonged activated partial thromboplastin time (APTT) and prothrombin time (PT), decreased fibrinogen level
  • Imaging: Presence of pleural effusion, ascites and/or gallbladder wall thickening, gallbladder wall thickened at >5 mm 

Classification 

WHO 2009 Classification of Dengue Infection

Based on the 2009 case classification by the WHO, patients are categorized depending on the patient’s severity level as severe dengue or non-severe dengue, either with or without warning signs.  

Dengue without Warning Signs  

Patients present with high fever (40°C/104°F) plus two of the following:

• Nausea or vomiting
• Rash
• Headache, eye pain, muscle ache, joint pain
• Positive tourniquet test 

Dengue with Warning Signs  

Patients present with signs of dengue with warning signs of severe infection in addition to any of the following:

• Severe abdominal pain or tenderness
• Persistent vomiting
• Clinical fluid accumulation (eg pleural effusion, ascites)
• Bleeding from the mucosa
• Lethargy or restlessness
• Hepatomegaly of >2 cm
• Increased hematocrit with rapid decrease in platelet count 

Severe Dengue  

Patients present with signs of dengue infection with at least one of the following:

• Severe plasma leakage leading to shock or fluid accumulation with respiratory distress
• Severe bleeding
• Severe organ involvement (aspartate aminotransferase [AST] or alanine aminotransferase [ALT] of ≥1000 units/L, impaired consciousness, organ failure)

The symptoms to watch out for include severe abdominal pain, persistent vomiting, tachypnea, bleeding gums or nose, fatigue, restlessness, and the presence of blood in vomitus or stool.  

Old Classification of Dengue Infection

The old classification of dengue infection is based on the 1997 classification scheme by the WHO.  

Undifferentiated Fever  

Undifferentiated fever may be the most common manifestation of dengue infection.  

Dengue Fever (DF) 

Dengue fever is an acute febrile illness with ≥2 of the following features:

• Headache, retro-orbital pain
• Myalgia, arthralgia
• Rash
• Nausea, vomiting
• Hemorrhagic manifestations
• Leukopenia, thrombocytopenia, or hematocrit rise by 5-10% 

Its occurrence is at the same location and time as other confirmed cases of dengue fever. 

Older children and adults present with mild febrile syndrome or high fever with abrupt onset. The fever may be biphasic (high fever that becomes normal then recurs to its previous degree) and usually lasts for 2-7 days. Patients may also present with severe headaches, pain behind the eyes, general malaise, muscle or joint pains, nausea or vomiting, and rash. Hemorrhagic manifestations include epistaxis, gingival bleeding, hematuria, menorrhagia, skin hemorrhages (petechiae, purpura, ecchymoses), and gastrointestinal bleeding (hematemesis, melena, hematochezia). Infants and young children commonly present with undifferentiated fever and maculopapular rashes. 

Atypical presentation of dengue fever includes acute abdominal pain, diarrhea, severe gastrointestinal hemorrhage, severe headache, convulsions, altered sensorium, encephalitic signs associated with or without intracranial hemorrhage, irregular pulse and heart rate, respiratory distress, fulminant hepatic failure, obstructive jaundice, raised liver enzymes, Reye syndrome, acute renal failure disseminated intravascular coagulation (DIC), and vertical transmission in newborns. 

Physical examination of patients suspected of dengue fever should include blood pressure (BP) measurement, hydration status, capillary refill time, and tourniquet test. The tourniquet test is performed by inflating the blood pressure cuff on the upper arm to a point midway between the systolic and diastolic pressures for 5 minutes. The test is positive when ≥20 petechiae/square inch is observed. 

Supportive serology includes a Coutination-inhibition (HI) antibody titer of ≥1:1280, comparable IgG titer with enzyme-linked immunosorbent assay (ELISA), and a positive IgM antibody test on a late acute or convalescent-phase serum specimen.

Confirmation is made by the presence of at least one of the following laboratory criteria:

• Isolation of the dengue virus from serum, cerebrospinal fluid (CSF), or autopsy samples
• Demonstration of a ≥4-fold rise in serum IgG or IgM antibody titers particular to dengue virus
• Demonstration of dengue virus Ag in autopsy tissue, serum, or CSF samples by immunohistochemistry, immunofluorescence, or ELISA
• Detection of dengue virus genomic sequences through reverse transcriptase-polymerase chain reaction (PCR) 

Dengue Hemorrhagic Fever (DHF)  

During the acute phase of the illness, it is difficult to distinguish dengue hemorrhagic fever from dengue fever and other febrile illnesses; thus, an accurate diagnosis can only be made once the fever remits. Major differentiating changes include abnormal hemostasis and plasma leakage into the abdominal and pleural cavities.  

The critical stage in dengue hemorrhagic fever is at the time of defervescence (ie the phase of plasma leakage), but signs of circulatory failure or hemorrhagic manifestations may occur from about 24 hours before to 24 hours after the temperature falls to normal.  

Patients with dengue hemorrhagic fever should present with the following:

• Fever, or history of acute fever, lasting 2-7 days, occasionally biphasic
• Hemorrhagic tendencies, evidenced by at least one of the following:
  • Positive tourniquet test
  • Petechiae, ecchymoses, or purpura
  • Bleeding from the mucosa, gastrointestinal tract, injection sites, or other locations
  • Hematemesis or melena
• Thrombocytopenia (≤100,000/mm³)
• Evidence of plasma leakage due to increased vascular permeability, manifested by at least one of the following:
  • A rise in the hematocrit ≥20% above average for the corresponding age, sex, and population
  • A drop in the hematocrit following volume-replacement treatment ≥20%
  • Signs of plasma leakage (eg pleural effusion, ascites, hypoproteinemia)

Physical examination of patients with dengue hemorrhagic fever includes a positive tourniquet test, wherein discrete fine petechiae are found scattered in the extremities, axillae, face, and soft palate which are seen during the early febrile phase. The increase in capillary fragility is reflected by a positive tourniquet test and easy bruising.  Blood pressure is decreased as an effect of plasma leakage into the extravascular compartment following an acute increase in vascular permeability.  

Laboratory examinations may include evidence of disseminated intravascular coagulation, thrombocytopenia on complete blood count (CBC), prolonged PT and partial thromboplastin time (PTT), and decreased fibrinogen level and increased level of fibrinogen degradation products. Other laboratory findings may include leukopenia and hemoconcentration (rising hematocrit). Imaging may show evidence of pleural effusion and ascites due to an acute increase in vascular permeability.  

Dengue hemorrhagic fever is classified into four grades of severity, where grades III and IV are considered dengue shock syndrome (DSS). The presence of thrombocytopenia with concurrent hemoconcentration differentiates grades I and II from dengue fever.

* DHF: Dengue Hemorrhagic Fever, DSS: Dengue Shock Syndrome

Dengue Shock Syndrome (DSS)  

Patients with dengue shock syndrome present with circulatory failure where the skin becomes cool, blotchy, and congested, circumoral cyanosis, rapid, weak pulse with narrowing of the pulse pressure, and hypotension with cold clammy skin. They may initially be lethargic then become restless and rapidly enter a critical stage of shock. They may also present with acute abdominal pain.  

Physical examination shows a rapid weak pulse with narrowing of the pulse pressure (<20 mmHg). Pleural effusion and ascites may also be detected by physical examination or radiography.  

The case definition of dengue shock syndrome is that all the four criteria for dengue hemorrhagic fever must be present, plus evidence of circulatory failure manifested by:

• Rapid and weak pulse, tachycardia
• Narrow pulse pressure (<20 mmHg) with increased diastolic pressure
• Hypotension for age
• Cold clammy skin, restlessness, lethargy 

As seen in laboratory examinations, the continuing drop in the platelet count concurrent with a rise in the hematocrit is an important indication of dengue shock syndrome.