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| REVIEW ARTICLE |
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| Year : 2017 | Volume
: 15
| Issue : 2 | Page : 95-105 |
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Dengue illness in children
Winsley Rose, J Ebor Jacob, Debasis Das Adhikari, Valsan Philip Verghese
Department of Child Health, Christian Medical College, Vellore, Tamil Nadu, India
| Date of Web Publication | 18-May-2017 |
Correspondence Address:
Winsley Rose
Department of Child Health, Christian Medical College, Vellore - 632 004, Tamil Nadu
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/cmi.cmi_25_17
Dengue fever is often a self-limiting illness of viral origin and is transmitted by mosquitoes. Children, especially those under 2 years of age and those with comorbid illnesses are particularly vulnerable. A small percentage of individuals with the infection may develop features of severe dengue (SD) which is potentially life threatening. Warning signs often precede the development of SD. The recognition of symptoms of SD fever and optimal fluid management are key factors in the treatment of this illness.
Keywords: Dengue, dengue hemorrhagic fever, dengue in children, treatment of dengue
How to cite this article:
Rose W, Jacob J E, Adhikari DD, Verghese VP. Dengue illness in children. Curr Med Issues 2017;15:95-105 |
| Introduction | |  |
Dengue is a mosquito-borne viral illness, transmitted by the female of Aedes mosquito, predominantly of Aedes aegypti species and to a lesser extent Aedes albopictus. The disease usually occurs in focal outbreaks in a geographical location and shows a seasonal incidence, more common following the rainy season. Dengue fever is often a self-limiting illness; however, some children progress to develop severe dengue (SD) which includes variants such as dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), both of which are life threatening. The recognition of warning signs, symptoms of SD fever, and optimal fluid management are key factors in the treatment of this illness. Children, especially those under 2 years of age and those with comorbid illnesses are particularly vulnerable. In this review, the diagnosis and protocols for the management of this illness are discussed.
| Epidemiology | | |
Globally, 3.9 billion people in 128 countries are estimated to be at risk of dengue infection.[1] An estimated 96 million (67–136 million) manifest clinically [2] with 500,000 people, predominantly children requiring hospitalization each year.
Although the number of cases reported worldwide has increased exponentially over the past decade, the case fatality rates (CFRs) have decreased over the years, from about 2.5% in 1985 to about 1.5% in 2009 [Figure 1]. One of the major reasons for this decrease in CFR has been a better understanding and implementation of fluid management in the treatment of dengue. In India and surrounding countries like Nepal, the mortality rate still remains around 2.5% among those affected during focal outbreaks of the disease, especially in villages and small towns.[3] Fatality is often a consequence of the severe forms of the disease – DHF and DSS. | Figure 1: Decreasing number of reported dengue cases and case fatality rates from South-East Asia.[3]
Click here to view |
| Virology | | |
Dengue is caused by a single-stranded RNA virus (family - Flaviviridae; genus - Flavivirus). They are small, enveloped viruses with three structural and seven nonstructural proteins and a single-stranded RNA genome.
Dengue infection - Key points
- Dengue is a mosquito-borne viral illness, transmitted by the female of Aedes mosquito, predominantly of Aedes aegypti species.
- Fever associated with headache and body ache is the most common presentation of this illness.
- Severe dengue with hemorrhagic symptoms and shock is seen in about 5% of primary infections.
- There are warning signs that precede the onset of hemorrhagic manifestations and shock. It is important, therefore, to identify children with these warning signs before the illness progresses.
- Manifestations of severe dengue often begin as the fever begins to subside (after 2–7 days of fever).
- Optimal fluid management and monitoring for warning signs and fluid status are the keys to the treatment of dengue infection.
- It is critical to understand that severe dengue usually occurs in three phases [Figure 4] because the body fluid status differs in each phase and fluid management has to be optimized according to the phase of the illness.
- Prophylactic platelet transfusion is unnecessary even when counts are very low if there is no evidence of significant bleeding.
There are four distinct serotypes of the virus that cause illness (DEN-V1, DEN-V2, DEN-V3, and DEN-V4). A fifth serotype was discovered in 2013.[4]
Lifelong immunity against a particular serotype is provided after recovery from infection due to that serotype. However, there is only partial and incomplete cross-immunity when infected by other serotypes. The first or primary infection with a serotype is typical of most viral infections and is often self-limiting. However, subsequent secondary infections by a different serotype vastly increase the risk of developing SD.[5] This risk depends on the serotype causing the secondary infection [Table 1].[6] | Table 1: Increase in risk of developing Severe Dengue in a repeat infection
Click here to view |
| Transmission | | |
Dengue is a mosquito-borne viral illness, transmitted by the female of Aedes mosquito, predominantly of A. aegypti species and to a lesser extent A. albopictus (also called the “tiger mosquito” because of its distinctive black and white stripes). This mosquito also transmits yellow fever, Zika, and Chikungunya infection.
The process of transmission starts when a mosquito bites a viremic host who has dengue virus in the circulation. The viremic host typically can transmit the virus through the Aedes mosquito from 2 days before developing symptoms to 4–5 days (maximum 12 days) after onset of symptoms (2–5 days). The virus has an “extrinsic incubation period (EIP)” of 8–12 days in the infected mosquito.[7] The EIP is the period between the time when a mosquito takes in blood from an infected person and the time when that mosquito becomes infectious. Following this, the mosquito is capable of transmitting the virus for the rest of its life.[5]
The virus replicates in the gut of the mosquito, then moves from the gut to the salivary gland of the mosquito from where it is transmitted to the bloodstream of the next person bitten. Once the virus enters the bloodstream of a new host, there is an intrinsic incubation period (IIP) for the virus, of 4–10 days, before symptoms appear (the IIP is the time between a human being infected and the onset of symptoms due to the infection).[5]
Education of the public regarding the life cycle and transmission of the virus is important in the prevention of transmission of the virus [Box 1].
| Pathophysiology of Dengue Infection | | |
Primary infection
The bite of the mosquito inoculates the virions into the skin, which go on to infect the dendritic cells (macrophages in the skin). The virions are transported through the lymphatic system into the draining lymph nodes and then into the bloodstream. The resulting viremia initiates a host immune response (both adaptive and innate immune response including production of interferons) which ultimately results in clearance of the viruses from the bloodstream. The liver is particularly involved in dengue virus infection. High liver enzymes may be seen in an infection though severe hepatic failure is rare.
SD with hemorrhagic symptoms and shock is seen in about 5% of primary infections. There are two main pathophysiological features in SD:[8]
- Increased vascular permeability that leads to plasma leak. This loss of plasma manifests as signs and symptoms of shock and fluid accumulation (edema, pleural effusion, ascites, etc.)
- Disorders of hemostasis – thrombocytopenia, coagulopathy, and vascular changes which manifest as hemorrhage.
Secondary infection
Primary infection with one of the four serotypes of dengue virus generally provides long-lasting immunity to subsequent infection by a virus of the same serotype. Despite some cross-immunity, there is a higher risk of developing SD in a secondary infection by a virus of another serotype. This is because the pathophysiology in this case is quite different from that of a primary infection [Box 2]. The antibodies developed during a primary infection combine with the virions (of another serotype) and form an antibody–virus complex. This complex enhances the infectivity of the virus and enables it to enter cellular compartments better. There are also a diminished antiviral immune response, an increased production of cytokines, and complement activation. The secondary infection ultimately results in an enhanced pro-inflammatory response, higher viral titers, increased vascular permeability, and coagulopathy. The last two in the list – enhanced vascular permeability (which causes leakage of plasma from capillaries into the extravascular space) and coagulopathy are responsible for the higher incidence of SD illness.[9]
| Clinical Features of Dengue | | |
Dengue fever affects people of all age groups but is particularly common in children. Many are infected without fever, thus allowing mosquitoes to continue the transmission chain.
The WHO classification of dengue involves two categories:[10],[11]
- Dengue fever and
- SD (including both DSS and DHF).
Dengue fever
In an outbreak, dengue fever may be suspected in children with the following symptoms and signs:[10],[11],[12]
- High-grade fever
- Headache
- Myalgia, and arthralgia
- Facial flushing
- Malaise and generalized body ache
- Retro-orbital eye pain and photophobia
- Rash [Box 4] and skin erythema
- Positive tourniquet test [Figure 2][13]
- Sore throat, an injected pharynx, and conjunctival injection in some cases
- Anorexia, nausea, and vomiting are common.
Laboratory investigations may indicate leukopenia, lymphocytosis, and thrombocytopenia.
Fever
Fever is a very common symptom in dengue infection. Headache and body ache are common. The acute febrile phase usually lasts 2–7 days, and in most instances, patients with dengue fever recover by 7 days. Fever that lasts more than 7 days is most likely not due to dengue virus and one has the look for other causes.
It can be difficult to distinguish dengue clinically from nondengue febrile diseases in the early febrile phase. A positive tourniquet test in this phase indicates an increased probability of dengue. These clinical features do not predict the severity of disease. Therefore, it is crucial to monitor for warning signs and other clinical parameters to recognize progression to the critical phase.
Severe dengue
SD (which includes DHF and DSS) is a serious illness which can be a life threatening. It is characterized by severe plasma leakage which can lead to shock, hemorrhagic manifestations, and multiorgan damage [Table 2] and [Figure 3]. Only about 5% of those who develop dengue fever progress to be have SD and there are risk factors [Box 3] that predispose some children to the severe illness.[10],[11]
Warning signs
Manifestations of SD often begin as the fever begins to subside (after 2–7 days of fever) and there are warning signs that precede the onset of hemorrhagic manifestations and shock. It is important, therefore, to identify children with these warning signs before the illness progresses [Table 3]. When the initial fever subsides, therefore, one has to be vigilant. Parents, in particular, should be made aware of the warning signs of SD in children so that they seek immediate medical attention because SD is a medical emergency.
Three phases of severe dengue
It is critical to understand that SD usually occurs in three phases [Figure 4] because the body fluid status differs in each phase, and fluid management has to be optimized according to the phase of the illness. The cardinal features of these phases are given below.[15] | Figure 5: Febrile rash. (From Malavige GN et al. Postgrad Med J 2004;. Used with permission)
Click here to view |
 | Figure 6: Convalescent rash (islets of white in a sea of red). (Photo by Premaratna R. Used under CC 4.0 licence)
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Febrile phase
This first phase is characterized by fever and its attendant problems such as febrile convulsions and dehydration. Optimal weight-based fluid replacement can help a child tide over this phase. Serum platelet counts may decrease during this phase and may manifest as minor hemorrhages.
Critical phase
This phase is characterized by two important pathological processes – (1) plasma leak from the intravascular compartment to the extravascular compartment and (2) coagulopathy. The child may be afebrile during this phase but will often continue to look sick.
Plasma leak manifests as edema, ascites, and pleural effusion. A child with edema may give the appearance of being fluid overloaded, while in reality, there is fluid loss. It is critical therefore that the treatment should involve replacement of the fluid deficit. Bleeding manifestations include hemorrhages in the gastrointestinal tract, mucosal surfaces, skin, and in severe cases may lead to hypovolemic shock. In severe cases, there may be multiorgan failure. The risk of death is highest in this phase.
Convalescence (reabsorption phase)
The child who has overcome the previous two phases now goes into a recovery phase lasting 2–4 days where there is stabilization of vital parameters. However, this is also the period when the excess extravascular fluid is being reabsorbed into the intravascular space which may lead to a fluid overload state. Care must be exercised therefore that the fluid replacement initiated in the earlier phase is appropriately reduced to avoid progression into pulmonary edema.
| Laboratory Investigations | | |
Confirmatory diagnosis
The following tests help in confirming the diagnosis:
- The isolation of the virus (serum, real-time polymerase chain reaction assay)
- Demonstration of a viral antigen - NS1 (serum, ELISA, or rapid test) or
- RNA in the tissue or serum or by
- Demonstration of rising titer of specific serum dengue antibodies.
Probable diagnosis
Demonstration of the presence of dengue IgM antibodies is not very specific but help in making a probable diagnosis of dengue. [Figure 7] describes the most appropriate laboratory tests for each phase of the illness.[16],[17] Tests that detect the antigens are most effective for diagnosis during the early part of the illness (febrile phase) while those that detect antibodies are most effective in the latter part, once the fever subsides. | Figure 7: Laboratory investigations in various stages of dengue infection.[16]
Click here to view |
During the critical phase, elevated hematocrit (Hct), low platelet count, progressive leukopenia with atypical lymphocytes, abnormal coagulation profile, hypoalbuminemia, hyponatremia, elevated liver enzymes, and metabolic acidosis are often present. Imaging features such as thickened gallbladder wall, pleural effusions (almost always right sided), and ascites may be present.
Supportive tests
- Complete blood count - hemoglobin (Hb)/Hct, white cell count, and platelet count
- Blood grouping and cross-matching
- Peripheral smear indicates the type of anemia and confirms leukopenia. The presence of giant platelets and clumps is indicative of good platelet function
- Serum electrolytes, urea, and creatinine
- Random blood sugar
- Liver and renal function tests
- Chest X-ray – to look for effusion [Figure 8] which is an important clinical indicator of plasma leak in SD. In many cases, the effusion is mild and can be missed in an erect position X-ray as the opacity may be confined to obliteration of the costophrenic angle. A chest X-ray taken in the supine position, in such cases, may reveal diffuse opacity on one side, also known as the veil sign [Figure 8].
 | Figure 8: Small right-sided pleural effusion in a supine child (veil sign).
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| Management of Dengue Infection | | |
Protocol for management
The following is a suggested practical approach to the management of a dengue outbreak in the community (based on the protocol followed by Christian Medical College, Vellore, Tamil Nadu, India). The guidelines are adapted from the WHO guidelines for the management of dengue.[7],[8],[10],[11],[17]
Children with probable dengue are categorized into three groups based on the severity of illness [Table 4]:[18]
- Group A – Probable dengue without warning signs
- Group B – Probable dengue with warning signs
- Group C – SD.
Dengue area
During outbreaks, a specific area is earmarked to cohort these children with suspected dengue to be monitored closely and give adequate oral rehydration and to do relevant investigations.
| Approach to Management of Dengue | | |
Quick assessment in emergency room
Step I (overall assessment)
- Ensure presumptive diagnosis of dengue: Case defi nitions are given above
- Clinical history:
- Date of onset of fever
- Oral intake – Has it been adequate?
- Warning signs [Table 3]
- Physical examination – Look for the following signs during examination
- Tachypnea and respiratory distress
- Hydration status
- Signs of perfusion
- Heart rate (HR)
- Pulse volume and rate in all limbs
- Blood pressure (BP) and pulse pressure
- Mental state
- Hepatomegaly, evidence of plasma leak – edema, ascites, pleural effusion
- Rash and bleeding manifestations.
- Laboratory investigations: Baseline Hb, white blood cell, and platelets. Discussion on investigations was given above.
Treatment of dengue - Key points
- No specific antiviral agents are available
- Avoid aspirin, nonsteroidal anti-inflammatory drugs – these can precipitate Gastrointestinal bleed and Reye's syndrome
- There is no role for steroids as there is no effect on mortality. (relative risk. [RR]: 0.68, 95% confidence interval: 0.42.1.11), or need for blood transfusion. (RR: 1.08, 0.52.2.24)*
- Prompt and meticulous fluid resuscitation is the most important aspect of management. Ringer's lactate as effective as colloids for initial resuscitation#
- Prophylactic platelet transfusion is unnecessary even when counts are very low if there is no evidence of significant bleeding.
*Panpanich R, et. al. Cochrane Database Syst Rev 2006;3:CD003488.
#Wills BA, et. al. N. Engl J Med 2005;353:877.89.
Step II - Assessment of phase and severity
- Determine the phase of illness - Febrile, critical, or recovery phase
- Categorize into groups: A, B, and C [Table 4]
- Make a decision if the child needs admission? If yes, where? - Inside emergency ward/dengue area/wards/high dependency unit (HDU)/pediatric Intensive Care Unit (PICU).
Step III - Management decisions [Table 5] and [Figure 9]
- Group A: Send home/observe outside emergency in dengue area
- Group B: In-hospital management (inside emergency in-patient area/wards)
- Group C: Emergency resuscitation and admission to HDU/PICU.
| Monitoring of Individuals With Suspected Dengue | | |
Children without features of shock
Monitor in the dengue area every 8 h
- Look for “warning signs”
- Check vital parameters - HR, capillary filling time, pulse volume, urine output, BP, and pulse pressure
- Hb/platelet count Q24H.
Volume replacement therapy in children with warning signs
Group B: Children with warning signs but not in shock
General principles:
- Isotonic crystalloids should be used during the critical phase (normal saline [NS] or 5% dextrose NS; if <6 months – ½ NS or ½ NS with 5% dextrose)
- In obese patients, ideal body weight should be used for calculation
- Rate of intravenous (IV) administration should be adjusted according to the clinical situation
- Prophylactic platelet transfusion not recommended. Even in the event of severe bleeding with low platelets, consider fresh frozen plasma (FFP) and then platelets.
Rate of IV fluid infusion is as follows:
- 8 ml/kg/h for 1–2 h, then reduce to
- 6 ml/kg/h for 2–4 h, then reduce to
- 4 ml/kg/h for 24–48 h.
This may be reduced further to fluid maintenance (according to Holliday and Segar formula) if vital signs stable and Hb/Hct are not rising. Plan to discontinue IV fluids in 48 h.
Monitor:
- Vital signs – BP, HR, respiratory rate, capillary refill time, and abdominal girth – Q24H
- Urine output – Q4H
- Hb – Q8H, if Hct rising, titrate fluids accordingly
- Platelet count – Q24H
- Also check glucose, electrolytes, calcium, creatinine, liver enzymes, prothrombin time (PT)/partial thromboplastin time, and chest X-ray.
Other supportive measures:
- Correct hypoglycemia and electrolyte/calcium abnormalities
- Injection Vitamin K1 if PT prolonged
- If severe bleeding with thrombocytopenia and other coagulopathy or a procedure to be done, consider blood products in the order of packed cells, FFP, and platelet transfusion; if blood products are not available to give whole blood; avoid platelets alone
- Antibiotics if bacterial infection/rickettsial infection is suspected.
Children with warning signs plus compensated shock (systolic blood pressure maintained but signs of reduced perfusion) [Figure 10][10] | Figure 10: Algorithm for fluid management of compensated shock: In infants and children.[10]
Click here to view |
- Initial IV infusion is given at 10 ml/kg/h over 1 h
- With clinical improvement, reduce to 5–7 ml/kg/h for 1–2 h, then reduce as for children not in shock (above)
- If no clinical improvement with initial IV infusion, start second IV bolus at 10–20 ml/kg/h and repeat Hb/Hct to decide on need for packed cell transfusion/inotropic support in PICU.
Children with warning signs plus hypotensive shock [if systolic blood pressure [Table 6] and [Figure 11][10] | Figure 11: Algorithm for fluid management in hypotensive shock – infants, children, and adults.[10]
Click here to view |
- Give initial IV bolus at 10 ml/kg
- Over 15 min
- If improving, further IV infusions may be continued as for compensated shock
- If not improving, repeat IV boluses as needed and transfer to PICU.
Oral rehydration therapy for children
Oral rehydration therapy may be given according to weight to [Table 7] children with signs of mild dehydration, without warning signs (at home), or with warning signs (in the observation areas/ward).
Monitoring - Children with warning signs inside emergency or in the ward
Children with warning signs need to be monitored for the following:
- Vital signs and signs of perfusion – Q2H [Table 8]
- Urine output – Q4H
- Blood glucose (infants/risk) – Q6H
- Hct – Q12H
- Platelets – Q24H
- Liver, renal, and coagulation profile as indicated.
| Indication for Platelets, Fresh Frozen Plasma, and Packed Cells | | |
Prophylactic platelet transfusion is unnecessary even when counts are very low without bleeding or shock (risk of volume overload).
Platelets are indicated only in severe bleeding. Even if there is bleeding, consider packed cells first.
Indications for platelet transfusion:
- Platelets <50,000/cmm with
- Severe bleeding (or)
- Invasive procedure is planned.
- Platelets <20,000/cmm with
- Severe bleeding (or)
- Clinically unstable patient (features of shock) (or)
- Associated risk factors present.
- Platelets <5000/cmm with minor bleeding [Figure 10] and [Figure 11].
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | | |
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| 12. | Wilder-Smith A, Schwartz E. Dengue in travelers. N Engl J Med 2005;353:924-32. [ PUBMED] |
| 13. | Malavige GN, Fernando S, Fernando DJ, Seneviratne SL. Dengue viral infections. Postgrad Med J 2004;80:588-601. [ PUBMED] |
| 14. | Vijayalakshmi AM, Jayavardhana A. Febrile rash and convalescent rash of dengue fever. Indian Pediatr 2013;50:717. |
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| 16. | Simmons CP, Farrar JJ, Nguyen VV, Wills B. Dengue. N Engl J Med 2012;366:1423-32. [ PUBMED] |
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]
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