Global and national perspectives of dengue prevalence
The incidence of dengue fever (DF) and its severe forms – dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS) – have dramatically increased globally in recent decades and is a major public health concern.1,2 Globally, dengue is noted to be the most rapidly spreading mosquito-borne viral disease.2 On an average, the annual number of DF/DHF cases continues to rise exponentially every decade; from 479,848 in 1990-1999 to 1,656,870 in 2000-2008.1 Alarmingly, the incidence of dengue has continued to rise from 2.2 million in 2010 to 3.2 million in 2015.2 Endemic in more than 100 countries, South-East Asia is thought to be one of the most seriously affected regions in the world.2 Curbing the spread of dengue is especially vital in South-East Asia as of the 2.5 billion global population living in dengue endemic countries and at risk of contracting DF/DHF, 1.3 billion live in South-East Asia.1
On the national front, the incidence of dengue in Malaysia continues to be on the rise from 32 cases per 100,000 population in 2000 to 361 cases per 100,000 population in 2014.3 The incidence of dengue was particularly higher in those aged 15 years and above, and a good 70-80% of dengue cases were reported from urban areas.3 In 2016, a total of 101,357 cases of dengue and 237 dengue-related deaths were reported in Malaysia, of which, 51.3% recorded from Selangor.2
Dengue virus and its transmission to humans
The dengue virus (DENV) belongs to the Flavivirus genus of single-stranded positive-sense RNA viruses, causing visceral and central nervous system diseases in humans.4 Dengue can be caused by any one of the four DENV serotypes; DENVs 1-4.4 The DENV serotypes differ from one another by 25-40% at the amino acid level and can be further separated into genotypes with a variability of up to 3%.4 Each serotype of the DENV can also be further divided into subtypes; three subtypes for DENV-1, six for DENV-2 (one in non-human primates), four for DENV-3 and four for DENV-4.1 Infection with any one serotype of the DENV confers lifelong immunity against that serotype and elicits cross-protection for a few months against the other serotypes.1 Severe forms of dengue such as DHF and DSS is caused by secondary infection with another serotype or multiple infections by different serotypes.1
DENVs are transmitted to humans following an infected mosquito bite, mainly by the female Aedes (Ae.) mosquitoes belonging to the subgenus Stegomyia.5 Ae. aegypti is regarded to be the most important epidemic vector of DENVs in the tropical and subtropical regions of the world, while other species such as Ae. albopictus, Ae. polynesiensis, member of Ae. scutellaris complex, and Ae. niveus have been reported to be secondary vectors.5
Clinical manifestations of dengue
A dengue infection has an incubation period of 4-7 days, resulting in a spectrum of illness which ranges from undifferentiated mild febrile illness to DF and severe disease forms (such as DHF and DSS), with or without plasma leakage and organ impairment.1,3
Undifferentiated ‘flu-like’ fever is usually seen in infants, children and adults with a primary DENV infection, whereby the fever is indistinguishable from other viral infections. Maculopapular rash may either appear during the fever or during defervescence.1
DF is common in older children, adolescents and adults. DF may be benign but is incapacitating with severe headache, muscle, joint and bone pains (break-bone fever).1 In certain instances, DF may result in unusual haemorrhage such as gastrointestinal bleeding, hypermenorrhoea and massive epistaxis.1
DHF is more common in children less than 15 years of age and is mostly associated with secondary DENV infections.1 The hallmarks of DHF include abnormal haemostasis and plasma leakage, with thrombocytopenia and elevated haemoconcentration preceding the onset of shock.1
Unusual manifestations of severe organ involvement have been reported in DHF as well as in patients with no evidence of plasma leakage.1 Most DHF patients with such unusual manifestations are either those with comorbidities, coinfections or complications of prolonged shock.1
Phases of a dengue infection3,6
Phase I: Febrile phase
Sudden high-grade fever which lasts for 2-7 days, often accompanied by facial flushing skin erythema, generalized body ache, vomiting, myalgia, arthralgia, retro-orbital eye pain, photophobia, and headache. Certain patients may present with sore throat, infected pharynx and conjunctival injection. The acute phase may also be associated with haemorrhagic symptoms such as petechiae, and spontaneous bleeding from the gastrointestinal tract, nose, gums and other mucosal sites. There will be a progressive decrease in total white cell count followed by a reduction in platelet levels.
Phase II: Critical phase
This phase usually occurs after the third day of fever (or earlier), lasting for 24-48 hours, and is indicated by the abatement of the fever (defervescence). The decrease in body temperature is associated with increased capillary permeability in certain patients – at this point the patient may deteriorate and manifest third space plasma leakage or organ dysfunction. Many patients recover spontaneously or after a short period of fluid or electrolyte therapy, while patients with more severe forms of plasma leakage may develop compensated or decompensated shock. Patients who present with abdominal pain, persistent vomiting, persistent diarrhoea, clinical fluid accumulation, mucosal bleed and tender liver, may be at high risk of dengue-related complications. Thrombocytopaenia, haemoconcentration, leukopenia with relative lymphocytosis, clotting abnormalities, elevated levels of transaminases, hypoproteinaemia and hypoalbuminemia can be observed during this phase.
Phase III: Recovery/Reabsorption phase
This phase succeeds the critical phase, during which plasma leakage stops and is followed by the reabsorption of extravascular fluid. General well-being of the patient improves, appetite is better, gastrointestinal symptoms improve, haemodynamic status stabilizes and diuresis follows. Certain patients may develop a rash (‘isles of white in a sea of red’) with generalized pruritus. The normalization of platelet count is followed by recovery of white cell count. Organ dysfunctions may worsen in certain cases.
Diagnostic markers of dengue
Non-structural protein 1 (NS1) antigen
The nucleocapsid of the DENV is embedded with M and E structural protein and seven non-structural proteins, one of which is the NS1 protein.7 The NS1 protein is an ideal diagnostic marker of infection as it is found at high levels in the blood and can be detected right from the onset of symptoms to ≥9 days post-onset of symptoms.6 NS1 can be detected prior to an antibody response, similar to viral ribonucleic acid (RNA).6
Diagnostic tests3:
In a primary dengue infection, IgM appears as early as day 3-5, peaks several weeks post-recovery, and remains at detectable levels for several months thereafter.6 IgG on the other hand, does not appear during the acute phase of a primary infection but rather results in a rapid anamnestic response around day 3-5 of a secondary DENV infection.6 The ratio of IgM and IgG during the acute phase of a dengue infection can provide an indication of either a primary or secondary infection.6
Diagnostic tests3:
Viral RNA is detectable right from the onset of illness and is sensitive, specific, fast and less complicated.6
Diagnostic test3:
Virus isolation is a conventional method to detect a DENV infection and has been widely replaced by RT-PCR and NS1 tests.6
Common haematological markers to monitor during in a patient with dengue3
Brief overview on the management of dengue
The management of a dengue infection is mainly symptomatic and supportive, comprising namely of fluid therapy and acetaminophen to treat fever and alleviate other symptoms.3 Drugs such as aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids must be avoided.8
Criteria for patients who can be treated at home3
Guidelines by WHO recommends the following principles for fluid therapy9:
References:
The incidence of dengue fever (DF) and its severe forms – dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS) – have dramatically increased globally in recent decades and is a major public health concern.1,2 Globally, dengue is noted to be the most rapidly spreading mosquito-borne viral disease.2 On an average, the annual number of DF/DHF cases continues to rise exponentially every decade; from 479,848 in 1990-1999 to 1,656,870 in 2000-2008.1 Alarmingly, the incidence of dengue has continued to rise from 2.2 million in 2010 to 3.2 million in 2015.2 Endemic in more than 100 countries, South-East Asia is thought to be one of the most seriously affected regions in the world.2 Curbing the spread of dengue is especially vital in South-East Asia as of the 2.5 billion global population living in dengue endemic countries and at risk of contracting DF/DHF, 1.3 billion live in South-East Asia.1
On the national front, the incidence of dengue in Malaysia continues to be on the rise from 32 cases per 100,000 population in 2000 to 361 cases per 100,000 population in 2014.3 The incidence of dengue was particularly higher in those aged 15 years and above, and a good 70-80% of dengue cases were reported from urban areas.3 In 2016, a total of 101,357 cases of dengue and 237 dengue-related deaths were reported in Malaysia, of which, 51.3% recorded from Selangor.2
Dengue virus and its transmission to humans
The dengue virus (DENV) belongs to the Flavivirus genus of single-stranded positive-sense RNA viruses, causing visceral and central nervous system diseases in humans.4 Dengue can be caused by any one of the four DENV serotypes; DENVs 1-4.4 The DENV serotypes differ from one another by 25-40% at the amino acid level and can be further separated into genotypes with a variability of up to 3%.4 Each serotype of the DENV can also be further divided into subtypes; three subtypes for DENV-1, six for DENV-2 (one in non-human primates), four for DENV-3 and four for DENV-4.1 Infection with any one serotype of the DENV confers lifelong immunity against that serotype and elicits cross-protection for a few months against the other serotypes.1 Severe forms of dengue such as DHF and DSS is caused by secondary infection with another serotype or multiple infections by different serotypes.1
DENVs are transmitted to humans following an infected mosquito bite, mainly by the female Aedes (Ae.) mosquitoes belonging to the subgenus Stegomyia.5 Ae. aegypti is regarded to be the most important epidemic vector of DENVs in the tropical and subtropical regions of the world, while other species such as Ae. albopictus, Ae. polynesiensis, member of Ae. scutellaris complex, and Ae. niveus have been reported to be secondary vectors.5
Clinical manifestations of dengue
A dengue infection has an incubation period of 4-7 days, resulting in a spectrum of illness which ranges from undifferentiated mild febrile illness to DF and severe disease forms (such as DHF and DSS), with or without plasma leakage and organ impairment.1,3
Undifferentiated ‘flu-like’ fever is usually seen in infants, children and adults with a primary DENV infection, whereby the fever is indistinguishable from other viral infections. Maculopapular rash may either appear during the fever or during defervescence.1
DF is common in older children, adolescents and adults. DF may be benign but is incapacitating with severe headache, muscle, joint and bone pains (break-bone fever).1 In certain instances, DF may result in unusual haemorrhage such as gastrointestinal bleeding, hypermenorrhoea and massive epistaxis.1
DHF is more common in children less than 15 years of age and is mostly associated with secondary DENV infections.1 The hallmarks of DHF include abnormal haemostasis and plasma leakage, with thrombocytopenia and elevated haemoconcentration preceding the onset of shock.1
Unusual manifestations of severe organ involvement have been reported in DHF as well as in patients with no evidence of plasma leakage.1 Most DHF patients with such unusual manifestations are either those with comorbidities, coinfections or complications of prolonged shock.1
Phases of a dengue infection3,6
Phase I: Febrile phase
Sudden high-grade fever which lasts for 2-7 days, often accompanied by facial flushing skin erythema, generalized body ache, vomiting, myalgia, arthralgia, retro-orbital eye pain, photophobia, and headache. Certain patients may present with sore throat, infected pharynx and conjunctival injection. The acute phase may also be associated with haemorrhagic symptoms such as petechiae, and spontaneous bleeding from the gastrointestinal tract, nose, gums and other mucosal sites. There will be a progressive decrease in total white cell count followed by a reduction in platelet levels.
Phase II: Critical phase
This phase usually occurs after the third day of fever (or earlier), lasting for 24-48 hours, and is indicated by the abatement of the fever (defervescence). The decrease in body temperature is associated with increased capillary permeability in certain patients – at this point the patient may deteriorate and manifest third space plasma leakage or organ dysfunction. Many patients recover spontaneously or after a short period of fluid or electrolyte therapy, while patients with more severe forms of plasma leakage may develop compensated or decompensated shock. Patients who present with abdominal pain, persistent vomiting, persistent diarrhoea, clinical fluid accumulation, mucosal bleed and tender liver, may be at high risk of dengue-related complications. Thrombocytopaenia, haemoconcentration, leukopenia with relative lymphocytosis, clotting abnormalities, elevated levels of transaminases, hypoproteinaemia and hypoalbuminemia can be observed during this phase.
Phase III: Recovery/Reabsorption phase
This phase succeeds the critical phase, during which plasma leakage stops and is followed by the reabsorption of extravascular fluid. General well-being of the patient improves, appetite is better, gastrointestinal symptoms improve, haemodynamic status stabilizes and diuresis follows. Certain patients may develop a rash (‘isles of white in a sea of red’) with generalized pruritus. The normalization of platelet count is followed by recovery of white cell count. Organ dysfunctions may worsen in certain cases.
Diagnostic markers of dengue
Non-structural protein 1 (NS1) antigen
The nucleocapsid of the DENV is embedded with M and E structural protein and seven non-structural proteins, one of which is the NS1 protein.7 The NS1 protein is an ideal diagnostic marker of infection as it is found at high levels in the blood and can be detected right from the onset of symptoms to ≥9 days post-onset of symptoms.6 NS1 can be detected prior to an antibody response, similar to viral ribonucleic acid (RNA).6
Diagnostic tests3:
- Rapid Combo Test (RCT) – Detects NS1 and dengue immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies.
- NSI antigen test by enzyme-linked immunosorbent assay (ELISA)
In a primary dengue infection, IgM appears as early as day 3-5, peaks several weeks post-recovery, and remains at detectable levels for several months thereafter.6 IgG on the other hand, does not appear during the acute phase of a primary infection but rather results in a rapid anamnestic response around day 3-5 of a secondary DENV infection.6 The ratio of IgM and IgG during the acute phase of a dengue infection can provide an indication of either a primary or secondary infection.6
Diagnostic tests3:
- RCT
- Dengue IgM test by ELISA
- Dengue IgG test by ELISA
Viral RNA is detectable right from the onset of illness and is sensitive, specific, fast and less complicated.6
Diagnostic test3:
- Real time reverse transcription polymerase chain reaction (RT-PCR)
Virus isolation is a conventional method to detect a DENV infection and has been widely replaced by RT-PCR and NS1 tests.6
Common haematological markers to monitor during in a patient with dengue3
- White cell count
- Platelet count
- Haematocrit
- Liver Function Test
- Renal profile
- Coagulation profile
- Lactate and blood gases
Brief overview on the management of dengue
The management of a dengue infection is mainly symptomatic and supportive, comprising namely of fluid therapy and acetaminophen to treat fever and alleviate other symptoms.3 Drugs such as aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids must be avoided.8
Criteria for patients who can be treated at home3
- Able to tolerate orally well, good urine output and no history of bleeding
- Absence of warning signs (refer to Box 1: Warning signs)
- Physical examination:
- Haemodynamically stable
- No tachypnoea or acidotic breathing
- No tender liver of abdominal tenderness
- No bleeding
- No sign of third space fluid accumulation
- Non-altered mental state
- Investigation: Stable serial haematocrit
- Absence of other criteria for admission (ie, comorbidities, pregnancy, social factors)
- Symptoms:
- Warning signs (refer to Box 1: Warning signs)
- Bleeding manifestations
- Unable to tolerate oral fluids
- Reduced urine output
- Seizure
- Signs:
- Dehydration
- Shock
- Bleeding
- Any organ failure
- Special situations:
- Comorbidities (eg, diabetes, hypertension, ischaemic heart disease, coagulopathy, morbid obesity, renal failure, chronic liver disease, chronic obstructive pulmonary disease (COPD))
- More than 65 years of age
- Patients on anti-platelet and/or anticoagulants
- Pregnant women
- Social factors which limit follow-up
- Laboratory criteria: Rising haematocrit accompanied by reducing platelet count
Guidelines by WHO recommends the following principles for fluid therapy9:
- Optimal oral fluid therapy. Intravenous fluid therapy is mandatory in cases of shock (DSS) severe vomiting, and prostration (unable to take fluids orally).
- First-line of choice of intravenous fluids are crystalloids.
- Colloids as second-line measures for patients in hypotensive states who are unresponsive to boluses of intravenous crystalloids.
- Transfusion with packed cells (5-10 ml/kg) and/or blood components should be administered to patients with significant bleeding. Not required by patients with mild bleeding.3
References:
- Comprehensive Guidelines for Prevention and Control of Dengue and Dengue Haemorrhagic Fever. World Health Organization. Available at: http://apps.searo.who.int/pds_docs/B4751.pdf. Accessed 24 July 2018.
- Ahmad R, et al. PLoS ONE 2018;13(2):e0193326.
- Management of dengue infection in adults (Third Edition 2015). Ministry of Health Malaysia. Available at: http://www.moh.gov.my/penerbitan/CPG/CPG%20Dengue%20Infection%20PDF%20Final.pdf. Accessed 24 July 2018.
- Diamond MS, et al. Cell 2015;162:488-492.
- Khetarpal N, et al. J Immunol Res 2016;Volume 2016:Article ID 6803098.
- Muller DA, et al. J Infect Dis 2017;215(S2):S89-S95.
- Beltrán-Silva SL, et al. Rev Med Hosp Gen Méx 2018;81(3):146-153.
- Dengue Treatment & Management. Medscape. Available at: https://emedicine.medscape.com/article/215840-treatment. Accessed 25 July 2018.
- Hasan S, et al. J Int Soc Prev Community Dent 2016;6(1):1-6.
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