Dengue haemorrhagic fever or dengue shock syndrome in children

Abstract

Introduction

Dengue haemorrhagic fever and dengue shock syndrome are major causes of hospital admission and mortality in children.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical question: What are the effects of supportive treatments for dengue haemorrhagic fever or dengue shock syndrome in children? We searched: Medline, Embase, The Cochrane Library, and other important databases up to March 2014 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found nine studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: adding blood component transfusion to standard intravenous fluids; adding corticosteroids or intravenous immunoglobulin to standard intravenous fluids; and crystalloids versus colloids.

Key Points

Infection with the dengue virus, transmitted by the Aedes mosquito, ranges from asymptomatic or undifferentiated febrile illness to fatal haemorrhagic fever, and affects up to 100 million people per year worldwide.

• Non-severe dengue fever is characterised by a sudden onset of high fever associated with any of the following signs and symptoms: rash, severe aches and pains, and any of the following warning signs, abdominal pain or tenderness, persistent vomiting, clinical fluid accumulation, mucosal bleeding, lethargy, restlessness, liver enlargement greater than 2 cm, and an increase in haematocrit concurrent with rapid decrease in platelet count. Presence of warning signs warrants strict observation.

• Severe dengue haemorrhagic fever (previously dengue haemorrhagic fever and dengue shock syndrome) is characterised by severe plasma leakage, severe bleeding, and severe organ involvement manifested as elevated liver enzymes, impaired sensorium, and myocarditis. Severe plasma leakage is manifested by a rise or drop in haematocrit, fluid in the lungs or abdomen leading to respiratory distress, and dengue shock syndrome.

• Dengue haemorrhagic fever and dengue shock syndrome are major causes of hospital admission and mortality in children. If untreated, mortality can be as high as 20%. With appropriate case management, mortality can be reduced to less than 1%, depending on the availability of appropriate supportive care.

Crystalloids seem as effective as colloids in children with moderately severe dengue shock syndrome. We found no RCTs comparing crystalloids versus colloids in children with severe dengue shock syndrome.

There is consensus that blood component transfusion (fresh frozen plasma, packed red blood cells, or platelets) should be added to intravenous fluids in children with coagulopathy or bleeding. The optimal time for beginning transfusion is unclear.

We don't know whether adding corticosteroids or intravenous immunoglobulin to standard intravenous fluids reduces the risks of shock, pleural effusion, or mortality.

About this condition

Definition

Dengue infection is a mosquito-borne arboviral infection. An important criterion to consider in the diagnosis of dengue infection is history of travel or residence in a dengue-endemic area within 2 weeks of the onset of fever. The spectrum of dengue virus infection ranges from an asymptomatic or undifferentiated febrile illness to severe infection. In 2009, the classification of dengue into dengue fever, dengue haemorrhagic fever, and dengue shock syndrome was simplified into non-severe and severe dengue. Non-severe dengue is further divided into two subgroups — patients with warning signs and those without warning signs. This revised classification is aimed at guiding clinicians in deciding where and how patients should be observed and managed. Criteria for diagnosis of probable dengue include history of travel or residence in a dengue-endemic area, plus high grade fever of acute onset and two of the following signs and symptoms: nausea/vomiting, rash, severe aches and pains (also called 'breakbone fever'), positive tourniquet test, leukopenia, and any warning sign. Presence of any of the following warning signs — abdominal pain or tenderness, persistent vomiting, clinical fluid accumulation, mucosal bleeding, lethargy, restlessness, liver enlargement greater than 2 cm, and an increase in haematocrit concurrent with rapid decrease in platelet count — will require strict observation and medical intervention. Criteria for severe dengue fever include severe plasma leakage, severe bleeding as evaluated by the clinician, and severe organ involvement. Severe plasma leakage is manifested by a rise or drop in haematocrit, fluid in the lungs or abdomen leading to respiratory distress, and dengue shock syndrome. Haemorrhagic manifestations include skin haemorrhages, mucosal and gastrointestinal tract bleeding, and pulmonary haemorrhage. Severe organ involvement is manifested by any of the following: elevated liver enzymes (AST, ALT >1000), impaired consciousness (dengue encephalopathy), and dengue myocarditis (see table 1 ). The illness usually begins abruptly, occurring in three phases: febrile, critical, and recovery. The critical phase sets in during defervescence, when capillary permeability is increased accompanied by haemoconcentration, leading to hypovolaemic shock that can result in organ impairment, metabolic acidosis, disseminated intravascular coagulation, and severe haemorrhage. This review deals with interventions for dengue haemorrhagic fever and dengue shock syndrome in children.

Table 1.

WHO suggested dengue case classification and levels of severity.

Criteria for dengue with or without warning signs		Criteria for severe dengue
Probable dengueLive in/travel to dengue-endemic areasFever and 2 of the following criteria: nausea, vomiting; rash; aches and pains; tourniquet test positive; leukopenia; any warning sign.Laboratory-confirmed dengue(important when no sign of plasma leakage)	Warning signs*Abdominal pain or tenderness; persistent vomiting; clinical fluid accumulation; mucosal bleed; lethargy, restlessness; liver enlargement >2 cm; laboratory: increase in HCT concurrent with rapid decrease in platelet count*(requiring strict observation and medical intervention)	Severe plasma leakageShock (DSS); fluid accumulation with respiratory distress Severe bleedingAs evaluated by clinicianSevere organ involvementLiver: AST or ALT >=1000; CNS: impaired consciousness; heart and other

Reproduced with permission of WHO. Dengue haemorrhagic fever: diagnosis, treatment, prevention and control. Geneva: WHO 2009

Incidence/ Prevalence

Dengue fever and dengue haemorrhagic fever are public health problems worldwide, particularly in low-lying areas where Aedes aegypti, a domestic mosquito, is present. Cities near to the equator but high in the Andes are generally free from dengue because Aedes mosquitoes do not survive at high altitudes. However, variations in the climate system (particularly climate warming) has increased the geographic distribution of Aedes mosquitoes. The highest published elevation records for Aedes aegypti in the Americas are 1700–2130 m for Mexico and 2200 m for Colombia. Worldwide, an estimated 50–100 million cases of dengue fever, and hundreds of thousands of dengue haemorrhagic fever, occur yearly. Recent estimates using novel mapping techniques (based on an extensive database of 10,000 clinical records) provided a global estimate of 390 million new infections per year, with symptomatic and asymptomatic dengue case burden at 96 and 294 million, respectively. Endemic regions are the Americas, South East Asia, the western Pacific, Africa, and the eastern Mediterranean. Major global demographic changes and their consequences (particularly, increases in the density and geographic distribution of the vector with declining vector control, unreliable water supply systems, increasing non-biodegradable container and poor solid waste disposal, increased geographic range of virus transmission due to increased air travel, and increased population density in urban areas) are responsible for the resurgence of dengue in the past century. The WHO estimates that global temperature rises of 1.0–3.5°C may increase transmission of dengue fever by shortening the extrinsic incubation period of viruses within the mosquito, adding 20,000–30,000 more fatal cases annually.

Aetiology/ Risk factors

Dengue virus serotypes 1–4 (DEN 1, 2, 3, 4) belonging to the flavivirus genus are the aetiological agents. These serotypes are closely related, but antigenically distinct. Aedes aegypti, the principal vector, transmits the virus to and between humans. Dengue haemorrhagic fever and dengue shock syndrome typically occur in children under the age of 15 years, although dengue fever primarily occurs in adults and older children. Important risk factors influencing who will develop dengue haemorrhagic fever or severe disease during epidemics include the virus strain and serotype, immune status of the host, age, and genetic predisposition. There is evidence that sequential infection or pre-existing antidengue antibodies increases the risk of dengue haemorrhagic fever through antibody-dependent enhancement. Diagnosis To confirm dengue infection, identification of virus/viral RNA/viral antigen and the detection of an antibody response are preferred than either approach alone. During the first 4 to 5 days of illness, while the patient is febrile, dengue infections may be diagnosed by virus isolation in cell culture, by detection of viral RNA by nucleic acid amplification tests, or by detection of viral antigens by ELISA or rapid antigen detection tests using serum or plasma and other tissues. After day 5, dengue viruses and antigens disappear from the blood co-incident with the appearance of specific antibodies. Hence, at the end of the acute phase of infection, serology is the method of choice for diagnosis. Antibody response to infection differs according to the immune status of the host. In primary dengue infection, the antibodies rise slowly. IgM antibodies are the first to appear, detectable in 50% of patients by days 3 to 5 after onset of illness, increasing to 80% by day 5, and 99% by day 10. IgM levels peak about 2 weeks after the onset of symptoms and then decline to undetectable levels over 2 to 3 months. Anti-dengue serum IgG is detectable at low titres at the end of the first week of illness, increasing slowly thereafter. Serum IgG remains detectable after several months, and probably even for life. During a secondary dengue infection antibody titres rise rapidly with IgG as the dominant immunoglobulin. IgG is detectable at high levels, even in the acute phase, and persists for periods lasting from 10 months to life. Early convalescent stage IgM levels are significantly lower in secondary infections than in primary ones and may be undetectable in some cases, depending on the test used. To distinguish primary and secondary dengue infections, IgM/IgG antibody ratios are commonly used.

Prognosis

Dengue fever is an incapacitating disease, but prognosis is favourable in previously healthy adults, although dengue haemorrhagic fever and dengue shock syndrome are major causes of hospital admission and mortality in children. Dengue fever is generally self-limiting, with less than 1% case fatality. The acute phase of the illness lasts for 2 to 7 days, but the convalescent phase may be prolonged for weeks associated with fatigue and depression, especially in adults. Prognosis in dengue haemorrhagic fever and dengue shock syndrome depends on prevention, or early recognition and treatment of shock. Once shock sets in, fatality may be as high as 12% to 44%. However, in centres with appropriate intensive supportive treatment, fatality can be less than 1%. There is no specific antiviral treatment. The standard treatment is to give intravenous fluids to expand plasma volume. People usually recover after prompt and adequate fluid and electrolyte supportive treatment. The optimal fluid regimen, however, remains the subject of debate. This is particularly important in dengue, where one of the management difficulties is to correct hypovolaemia rapidly without precipitating fluid overload. WHO guidelines published in 2009 provide guidance on fluid management and blood transfusions.

Aims of intervention

To prevent mortality and improve symptoms, with minimal adverse effects.

Outcomes

Mortality; symptom severity (including recurrence of shock, duration of shock, fluid requirements, length of hospital stay, need for blood transfusion, complications, and symptom relief); adverse effects.

Methods

BMJ Clinical Evidence search and appraisal March 2014. The following databases were used to identify studies for this systematic review: Medline 1966 to March 2014, Embase 1980 to March 2014, and The Cochrane Database of Systematic Reviews 2014, issue 3 (1966 to date of issue). Additional searches were carried out in the Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment (HTA) database. We also searched for retractions of studies included in the review. Titles and abstracts identified by the initial search, run by an information specialist, were first assessed against predefined criteria by an evidence scanner. Full texts for potentially relevant studies were then assessed against predefined criteria by an evidence analyst. Studies selected for inclusion were discussed with an expert contributor. All data relevant to the review were then extracted by an evidence analyst. Study design criteria for inclusion in this review were: published RCTs and systematic reviews of RCTs in the English language, any level of blinding (including open studies) containing at least 20 individuals (at least 10 per arm) of whom at least 80% were followed up. There was no minimum length of follow-up. We included RCTs and systematic reviews of RCTs where harms of an included intervention were assessed, applying the same study design criteria for inclusion as we did for benefits. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA that are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table.

GRADE Evaluation of interventions for Dengue haemorrhagic fever or dengue shock syndrome in children.

Important outcomes	Mortality, Symptom severity
Studies (Participants)	Outcome	Comparison	Type of evidence	Quality	Consistency	Directness	Effect size	GRADE	Comment
What are the effects of supportive treatments for dengue haemorrhagic fever or dengue shock syndrome in children?
3 (655)	Symptom severity	Crystalloids versus colloids	4	0	0	–1	0	Moderate	Directness point deducted for small RCTs (may have been underpowered to detect a clinically significant difference in outcomes)
3 (655)	Mortality	Crystalloids versus colloids	4	0	0	–2	0	Low	Directness points deducted for RCT being underpowered to detect difference in outcome (1 event only) and no statistical analysis between groups
2 (89)	Symptom severity	Adding corticosteroids to standard intravenous fluids versus adding placebo or no corticosteroids	4	–3	0	–2	0	Very low	Quality points deducted for sparse data and methodological weaknesses (open label trial with unclear randomisation and allocation concealment); directness points deducted for baseline differences between groups and disparity in numbers of participants in comparator groups
4 (284)	Mortality	Adding corticosteroids to standard intravenous fluids versus adding placebo or no corticosteroids	4	–3	–1	–2	0	Very low	Quality points deducted for methodological weaknesses (open label trial with unclear randomisation and allocation concealment, and disparities in reporting of results in text article and table of results); consistency point deducted for conflicting results; directness points deducted for baseline differences between groups and disparity in numbers of participants in comparator groups
1 (31)	Symptom severity	Adding intravenous immunoglubulin (IVIG) to standard intravenous fluids versus no IVIG	4	–1	0	–2	0	Very low	Quality point deducted for sparse data; directness points deducted for population not having fever or shock and limited outcomes (non-clinical)

We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.

Glossary

Low-quality evidence

Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Moderate-quality evidence

Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Tourniquet test

A test performed by inflating the blood pressure cuff to a point midway between systolic and diastolic pressures for 5 minutes. It involves then deflating the cuff, waiting for the skin to return to its normal colour, and then counting the number of petechiae visible in a 2.5 cm square in the ventral surface of the forearm. Twenty or more petechiae in square patch (6.25 cm²) constitutes a positive tourniquet test.

Very low-quality evidence

Any estimate of effect is very uncertain.

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.