Dengue viral infection in children: a perspective
- 1Department of Pediatrics, Kanchi Kamakoti CHILDS Trust Hospital and CHILDS Trust Medical Research Foundation, Chennai, Tamil Nadu, India
- 2Department of Pediatric Intensive Care, Kanchi Kamakoti CHILDS Trust Hospital and CHILDS Trust Medical Research Foundation, Chennai, Tamil Nadu, India
- Correspondence to Dr S Balasubramanian, Departments of Pediatrics, Kanchi Kamakoti CHILDS Trust Hospital and CHILDS Trust Medical Research Foundation, 12, Nageswara Road, Nungambakkam, Chennai, Tamil Nadu 600034, India;
- Accepted 15 June 2012
- Published Online First 17 July 2012
Dengue is a vector-borne viral infection of global importance. Several pathogenetic mechanisms such as immune enhancement and selection pressure have been proposed and febrile, critical and recovery phases have been identified. A new classification proposed by WHO has recently been introduced where definitions have been changed to ‘probable dengue’, ‘dengue with warning signs’ and ‘severe dengue’. The majority of dengue viral infections are self-limiting, but complications have high morbidity and mortality. The diagnosis of dengue viral infection is essentially clinical, although confirmation requires laboratory tests including serology, NS1 antigen detection, PCR and viral cultures. There are no specific anti-dengue drugs and treatment is basically supportive and consists of early recognition of complications and appropriate fluid therapy. A number of candidate vaccines are under development.
Dengue is endemic in Asia, Southeast Asia, several southern and central Pacific countries and the Americas, with several outbreaks in India.1 Over 2.5 billion people (more than 40% of the world's population) are now at risk from dengue. WHO currently estimates that 50–100 million dengue infections may be occurring worldwide each year. An estimated 500 000 people with severe dengue require hospitalisation annually, a large proportion of whom are children and about 2.5% of those affected die.2
Recent studies indicate higher incidence in infancy,3 although the severity of illness among adults is increasing and has higher case-fatality rates (CFR)4; this age shift is obvious in some endemic Southeast Asian countries.5 There are racial differences in mortality and morbidity with lower infection rates and case fatality in black than in white patients.6 It has also been reported that the disease is more severe in females than males, although the incidence is higher in males.7 This has been attributed to more competent immune responses in females, resulting in greater production of cytokines and a tendency of capillary beds in females to increased permeability.8 The overall CFR in the South-East Asia Region is now less than 1%.9
Several theories seek to explain the pathogenesis including the ‘immune enhancement hypothesis’ and the ‘selection pressure hypothesis’.10–12 The immune enhancement hypothesis posits that patients with a second infection with a heterologous dengue serotype have a higher risk of developing severe dengue.11 The existing heterologous dengue antibody recognises the invading virus and establishes an antigen–antibody complex, which binds to the Fc receptor on the cell membrane of leukocytes. The virus freely replicates through antibody dependent enhancement. Anti-dengue virus antibodies cross-react with platelets, clotting factors and endothelial cells in humans.12 Anti-NS1 antibodies induce apoptosis in endothelial cells and increase vascular permeability, leading to hypovolaemia and shock. The selection pressure hypothesis claims that dengue virus varies and mutates as a result of selection pressure as it replicates in humans and/or mosquitoes. Some virus strains also have greater epidemic potential.12
The mechanisms leading to severe illness are not well defined but the immune response, the genetic background of the individual and the virus characteristics may all contribute to the development of severe dengue. A transient and reversible imbalance of inflammatory mediators, cytokines and chemokines occurs during severe dengue, probably driven by a high early viral burden, and leads to dysfunction of vascular endothelial cells, derangement of the coagulation system resulting in plasma leakage, shock and bleeding. Re-infection causes more severe disease and it is suggested that a host immunologically primed by one of the three other types of dengue virus might mount an immunological response which is more florid leading to severe dengue and complications.
A low incidence of dengue fever in travellers in comparison to the population in endemic areas has been reported, most likely because of the absence of pre-existing antibodies given the traveller's lack of previous exposure. However, a secondary response may not be the sole risk factor for more severe disease.13
While most patients with dengue recover following a self-limiting non-severe clinical course, a small proportion progress to severe disease. Dengue is a dynamic disease which may have three stages: febrile, critical and recovery. The febrile phase can last for 2–7 days, the critical phase may occur anywhere between 3 and 7 days after the start of illness, and the recovery phase occurs 2–3 days after the critical phase.14 Dengue has a wide spectrum of clinical presentations, often with unpredictable clinical evolution and outcome.
Children are more likely to develop shock because of their intrinsically more permeable micro-vasculature, although major bleeding, encephalopathy and liver involvement are more common in adults. Petechiae, melena, headache, retro-orbital pain, myalgia, joint pain, nausea and vomiting have been observed more commonly in adults in contrast to more frequent occurrence of epistaxis, oliguria and liver enlargement in children.15
Changes in the epidemiology of dengue, as described above, led to problems with the use of the earlier WHO classification which grouped symptomatic dengue virus infections into three categories: undifferentiated fever, dengue fever and dengue haemorrhagic fever (DHF).16 Many problems with this classification have been reported17–21 including difficulty classifying all cases precisely, epidemiological changes with increasing age, classifying the severity of dengue based on primary or secondary presentation, and the presence of secondary infections which play a major role in morbidity.22 A negative tourniquet test may not be sufficient to exclude a diagnosis of DHF in a febrile patient, necessitating redefinition of clinical criteria.23
A WHO supported prospective multicentre clinical study in endemic regions concluded that severe dengue and non-severe dengue could be clearly distinguished by combining clinical and/or laboratory parameters. The revised classification is more practical in terms of decision-making, categorisation of severity and planning management (figure 1) and also makes surveillance easier. The most important management strategy in dengue is early recognition of the different phases of the disease, which are clearly elucidated along with rational management algorithms in the revised classification.14
From a practical point of view, serial haematocrits are very useful since they can be performed every few hours to monitor the development or severity of leakage. A micro-haematocrit centrifuge should be considered an essential piece of equipment on any ward treating patients with severe dengue.
Accumulation of fluid in multiple body compartments becomes detectable typically at the time fever disappears and is well demonstrated on both CT and ultrasound examinations.24 Ultrasonography has been reported to be superior to laboratory parameters and radiography in detecting plasma leakage.25 Gallbladder wall thickening is significantly associated with severe dengue, along with thrombocytopenia and elevated haematocrit or haemoconcentration.26
Primary infections with dengue fever and dengue-like diseases are usually self-limiting and benign. Fluid and electrolyte losses, hyperpyrexia and febrile convulsions are the most frequent complications in infants and young children. Epistaxis, petechiae and purpuric lesions are uncommon but may occur at any stage. In adults and possibly in children, underlying conditions may lead to clinically significant bleeding. Some atypical manifestations have been observed but may be unrecognised and under-reported, although their detection is essential for clinical diagnosis and appropriate management, especially given the global health problems caused by dengue.27
The most dreaded complication is haemodynamic compromise leading to hypovolaemic or septic shock. Other complications are described in table 1.
Laboratory confirmation of dengue infection is crucial as the broad spectrum of clinical presentations, ranging from mild febrile illness to several severe syndromes, can make accurate diagnosis difficult. Early laboratory confirmation of the clinical diagnosis can be valuable because some patients quickly progress from mild to severe disease and sometimes death.
Dengue can be diagnosed through isolation of the virus, by serological tests or by molecular methods. Currently, virus isolation and serotype identification, nucleic acid detection, antigen detection, various antibody tests (IgM ELISA, IgM Rapid test and IgG ELISA by paired sera, haemagglutination inhibition or neutralisation test) are available (table 2).28 MAC-ELISA has a sensitivity and specificity of approximately 90% and 98%, respectively.29
Acute infection with dengue virus is confirmed when the virus is isolated from serum or autopsy tissue specimens, or the specific dengue virus genome is identified by reverse transcription-PCR (RT-PCR) from serum or plasma, cerebrospinal fluid or autopsy tissue specimens during an acute febrile illness. Methods such as one-step, real time RT-PCR or nested RT-PCR are now widely used to detect dengue viral genes in acute-phase serum samples. Current PCR tests are 80–90% sensitive and >95% specific.29
Facilities for viral culture and molecular methods for diagnosis confirmation are not readily available in most parts of the world, although they have definite advantages over conventional serological tests in the first 5 days of illness.
The DENCO (Dengue and Control) Study concluded that a positive PCR or positive viral culture, or IgM in paired sera, IgG seroconversion in paired sera or a fourfold IgG titre increase in paired sera is confirmatory for dengue viral infection. The presence of IgM in a single serum sample or IgG in a single serum sample with a haemagglutination inhibition titre of 1280 or higher was considered highly suggestive of dengue viral infection.30 The addition of an IgM/G component to NS1 testing improves diagnostic sensitivity above NS1 testing alone and probably is the most practical option for the diagnosis of dengue infection.31
For a disease that has complex manifestations, management is relatively simple, inexpensive and very effective in saving lives as long as correct and timely interventions are instituted. The key is early recognition and understanding of the clinical problems during the different phases of the disease, resulting in a rational approach to case management and a good clinical outcome.
Depending on the clinical manifestations and other circumstances, patients may be categorised into the following groups:
Group A: outpatient management with instructions
Group B: inpatient management
Group C: emergency treatment and urgent referral.
Group A: outpatient management with instructions (for those who can be sent home)
These patients should tolerate oral fluids, must pass urine at least once every 6 h and must not have any warning signs. They should be reviewed daily with a clinical examination and laboratory assessment. They should be encouraged to take oral rehydration solution and fruit juice to replace losses from fever and vomiting and reduce the risk of hospitalisation. Paracetamol is the preferred antipyretic with a minimum dosing interval of 6 h. Non-steroidal anti-inflammatory drugs may aggravate gastritis and/or bleeding and are to be avoided.
Caregivers must be informed that the patient should be brought to hospital immediately if any of the following occur: no clinical improvement, deterioration around the time of defervescence, severe abdominal pain, persistent vomiting, cold and clammy extremities, lethargy or irritability/restlessness, bleeding (eg, black stools or coffee-ground vomiting) or failure to pass urine for more than 4–6 h.
Group B: those who should be admitted to hospital
This group includes those with warning signs, co-morbid conditions or social situations where adequate home care cannot be ensured. Those without warning signs should be treated with oral fluids or just enough fluids to ensure good perfusion and should be monitored closely.
Choice of intravenous fluids
Most studies on the role of different fluids in the treatment of dengue infection32–34 found no difference in terms of recovery from shock or outcome, although colloids have been reported to provide the most rapid normalisation of the haematocrit and restoration of the cardiac index, without adverse effects.32 The current WHO guidelines recommend the use of either isotonic crystalloid or colloid fluids for the treatment of hypotensive shock.
Group C: those who require emergency treatment for severe dengue
This group includes patients with severe plasma leakage, haemorrhage or organ impairment and should be managed in a hospital with good intensive care facilities and access to blood transfusion. Children in group C require urgent intravenous resuscitation with crystalloids or colloids, aimed at maintaining adequate perfusion and urine output and improving tachycardia. In patients with compensated shock, fluids are started at a rate of 5–10 ml/kg/h and titrated based on clinical response and serial haematocrit measurements. Improvement is indicated by stable perfusion with good urine output and decreasing haematocrit.
Patients with hypotensive shock should receive boluses of intravenous isotonic crystalloid or colloid solution at a rate of 10–20 ml/kg over 15 min. Further fluids are adjusted based on the response and serial haematocrit measurements. Lack of improvement is indicated by persistent shock, narrowed pulse pressure, worsening metabolic acidosis and increasing haematocrit. A falling haematocrit at this stage may indicate haemorrhage and should be treated with blood transfusion (fresh whole blood or packed red blood cells).
Management of complications
Patients with severe dengue may have myocardial dysfunction in the form of decreased left ventricular ejection and cardiac index35–37 manifesting as hepatomegaly and tachycardia unresponsive to fluid therapy. These patients may respond to careful use of inotropic agents and vasodilators, after adequate fluid resuscitation. Myocardial dysfunction in dengue is transient and heart function usually returns to normal in survivors.
Patients who develop respiratory distress or failure because of shock or third spacing require oxygen and may benefit from nasal continuous positive airway pressure (NCPAP).38 Patients who deteriorate further with or without NCPAP, should be mechanically ventilated early. Patients with abdominal compartment syndrome will benefit from abdominal paracentesis. Occasionally, severe pleural effusions may require drainage with a small-bore catheter.
Treatment of haemorrhagic complications
Risk factors for haemorrhage include prolonged shock, hypotension, acidosis, liver and/or renal impairment or prior administration of non-steroidal anti-inflammatory drugs. External or internal haemorrhage should be treated with transfusion of fresh packed red blood cells 5–10 ml/kg or fresh whole blood 10–20 ml/kg. Attempts to increase platelet counts via transfusion in the absence of major haemorrhage have not protected against bleeding in dengue. Rather, early recognition of dengue, especially severe dengue and DHF, with prompt correction of haemodynamic parameters, remains the cornerstone of treatment to avoid haemorrhage and ensure good clinical outcomes.39 Intramuscular injections should be avoided and procedures such as the insertion of nasogastric tubes should performed with great care. Data on recombinant factor VII (rfVIIa) suggest that it may be useful for stopping active bleeding, although no mortality benefit has been demonstrated.40 ,41 Similarly, anti-D immunoglobulin may be useful for increasing the platelet count in Rh positive patients.42
Occasionally patients with renal failure may require dialysis. Continuous veno-venous haemofiltration is preferred since insertion of a peritoneal dialysis catheter may result in bleeding. Antibiotics are indicated only if secondary bacterial infection is suspected or if the presentation is atypical.
Illnesses that mimic DHF include leptospirosis and scrub typhus. There are no data to support the use of intravenous immunoglobulin in the treatment of dengue infection. Positive results from the use of desmopressin, high-dose immunoglobulin and activated factor VII on haemostasis have been reported.43 ,44 There is no evidence to support the use of corticosteroids in the management of severe dengue.
Currently there are no drugs specific for dengue. The potential targets of anti-dengue drugs include NS3, NS5 antigens, protein–protein interactions within the replicative complex and envelope protein. Inhibition of replication by 5-aza 7-deazaguanosine is being tested in an infected-cell-based assay.45 The ligand n-octyl-β-d-glucoside (βOG) is being developed as an inhibitor of envelope protein.46
Prevention and vaccination
Over the last 50 years three main methods (chemical control, environmental control and biological control) have been used to combat the dengue vector, the Aedes aegypti mosquito, but there is still no universal consensus on the best method of control. Even with community compliance, insecticidal spray may not reach all breeding sites and the mosquito population rebounds within a couple of weeks, thus rendering it an ineffective control strategy. Environmental management can be divided into three sub-groups: environmental modification, environmental manipulation and changes to human habitats and behaviour. However, compliance and enforcement of environmental management schemes may be difficult to achieve. This may be due to lack of cooperation and communication between the various levels of government involved, or lack of education about the importance of widespread compliance. Biological control involves the introduction of organisms that feed upon A aegypti including invertebrate copepods introduced into water storage tanks and larvivorous fish (Gambusia). Biocontrol agents do not adversely affect the ecosystem as they do not contaminate the environment chemically and are often species specific. However, the costs of rearing these species can be high and they are often location specific.
Vaccines for dengue
As all four dengue serotypes co-circulate, vaccines need to be tetravalent. Current candidate vaccines include live attenuated vaccines, chimeric live attenuated vaccines, inactivated or sub-unit vaccines and nucleic acid-based vaccines. Live attenuated vaccines are in phase 1 testing. Vaccines in advanced preclinical development include DEN-DEN chimaeras, wherein the prM and E protein genes of DEN-1, DEN-3 and DEN-4 have been inserted into the infectious clone of PDK-passaged attenuated DEN-2 (PDK53). Vaccine development is summarised in table 3.47
Future of dengue viral infections
Despite our increased understanding of both the virological and host factors of dengue virus and human infection, questions remain about the virus–host interactions that result in severe dengue. There are still many challenges in the effort to control dengue virus, including prediction of dengue transmission dynamics, the development of tractable, informative animal models, the development of novel therapies, and the ultimate challenge, the development of a dengue virus vaccine that provides durable long-lasting protective immunity against infection and illness.
One of the most important tasks for the future will be to identify the small group of children who are likely to develop severe dengue early and then focus efforts on preventive treatment, possibly with immune modulation and/or antivirals.
The unpredictable nature of the clinical manifestations and complications of dengue viral infection in children pose diagnostic and therapeutic challenges for paediatricians worldwide, particularly in countries with difficulties delivering high quality medical care. Added to this are the lack of understanding of the pathogenesis of this disease, particularly with regard to host-related factors associated with the severity of disease, and difficulties preventing this old disease spreading with a new vengeance.
Contributors SB conceived the idea for the article, contributed to the literature search and final editing of the article and acts as guarantor. BR contributed to the article and final editing of the article. SA carried out the literature search and helped to prepare the manuscript.
Competing interests None.
Provenance and peer review Commissioned; externally peer reviewed.