Abstract
Introduction
Dengue haemorrhagic fever and dengue shock syndrome are major causes of hospital admission and mortality in children. Up to 5% of people with dengue haemorrhagic fever die of the infection, depending on availability of appropriate supportive care.
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 June 2008 (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 13 systematic reviews or RCTs 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 carbazochrome sodium sulfonate, corticosteroids, or intravenous immunoglobulin to standard intravenous fluids; adding recombinant-activated factor VII to blood component transfusion; colloids; crystalloids; and intravenous fluids.
Key Points
Infection with the dengue virus, transmitted by mosquito, ranges from asymptomatic or undifferentiated febrile illness to fatal haemorrhagic fever, and affects up to 100 million people a year worldwide.
Dengue haemorrhagic fever is characterised by: a sudden onset of high fever; haemorrhages in the skin, gastrointestinal tract, and mucosa; and low platelet counts. Plasma leakage results in fluid in the abdomen and lungs. It typically occurs in children under 15 years.
Severe dengue haemorrhagic fever is called dengue shock syndrome.
Dengue haemorrhagic fever and dengue shock syndrome are major causes of hospital admission and mortality in children. Up to 5% of people with dengue haemorrhagic fever die of the infection, depending on availability of appropriate supportive care.
Intravenous fluids are the standard treatment to expand plasma volume and are likely to be beneficial, but studies to demonstrate their effectiveness would be unethical.
Crystalloids seem as effective as colloids in children with moderately severe dengue shock syndrome, although we don't know whether they are beneficial in 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 carbazochrome sodium sulfonate (AC-17), corticosteroids, intravenous immunoglobulin, or recombinant activated factor VII to standard intravenous fluids reduces the risks of shock, pleural effusion, or mortality. We also don't know whether adding recombinant activated factor VII toblood component transfusion reduces the risk of bleeding episodes, shock, or mortality.
About this condition
Definition
Dengue infection is a mosquito-borne arboviral infection. The spectrum of dengue virus infection ranges from asymptomatic or undifferentiated febrile illness to dengue fever and dengue haemorrhagic fever or dengue shock syndrome. 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. Dengue fever is an acute febrile illness whose clinical presentation varies with age. Infants and young children may have an undifferentiated febrile disease with a maculopapular rash. Children aged 15 years or older and adults may have either a mild febrile illness, or the classic incapacitating disease (also called “breakbone fever”), presenting with high fever of sudden onset, and non-specific signs and symptoms of: severe headache; pain behind the eyes; muscle, bone, or joint pains; nausea; vomiting; and rash. Dengue haemorrhagic fever is characterised by four criteria: acute onset of high fever; haemorrhagic manifestations evidenced by a positive tourniquet test, skin haemorrhages, mucosal and gastrointestinal tract bleeding; thrombocytopenia; and evidence of plasma leakage manifested by a rise or drop in haematocrit, fluid in the lungs or abdomen, or hypoproteinaemia. Dengue haemorrhagic fever is classified into four grades of severity (see table 1 ). Presence of thrombocytopenia and haemoconcentration differentiates dengue haemorrhagic fever grades I and II from dengue fever. Grades III and IV dengue haemorrhagic fever are considered dengue shock syndrome.This review deals with interventions for dengue haemorrhagic fever and dengue shock syndrome in children.
Table 1.
WHO grading of severity of dengue haemorrhagic fever.
| Grade | Description |
| Grade I | Fever accompanied by non-specific constitutional symptoms; the only haemorrhagic manifestation is a positive tourniquet test, easy bruising, or both |
| Grade II | Spontaneous bleeding in addition to the manifestations of Grade I, usually in the form of skin and other haemorrhages |
| Grade III | Circulatory failure manifested by a rapid, weak pulse and narrowing of pulse pressure or hypotension, with the presence of cold, clammy skin, and restlessness |
| Grade IV | Profound shock with undetectable blood pressure or pulse |
Reproduced with permission of WHO. Dengue haemorrhagic fever: diagnosis, treatment, prevention and control. Geneva: WHO 1997
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 free from dengue because Aedes mosquitoes do not survive at high altitudes. Worldwide, an estimated 50–100 million cases of dengue fever, and hundreds of thousands of dengue haemorrhagic fever, occur yearly. 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. Ae 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.
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 2–7 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. Case fatality ranges from 2.5–5.0%. Once shock sets in, fatality may be as high as 12–44%. 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.
Aims of intervention
To prevent mortality and improve symptoms, with minimal adverse effects.
Outcomes
Mortality; recurrence of shock; symptom relief; renal failure; length of hospital stay; time to recovery; time off work; need for blood transfusion; fluid requirements; adverse effects (bleeding, fluid overload, hypersensitivity reactions, and secondary infections). Secondary outcomes include development of shock and development of pleural effusion.
Methods
Clinical Evidence search and appraisal June 2008. The following databases were used to identify studies for this systematic review: Medline 1966 to June 2008, Embase 1980 to June 2008, and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials 2008, Issue 2 (1966 to date of issue). An additional search was carried out of the NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA). We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributor for additional assessment, using pre-determined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews of RCTs and RCTs in any language and containing more than 20 individuals of whom more than 80% were followed up. We may use sensitivity analysis that supports the strength of conclusions when losses to follow-up seem to be significant. Length of follow-up required to include studies was at least from admission until discharge from hospital or occurrence of a main outcome. We did not exclude RCTs described as “open”, “open label”, or not blinded. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. The author also retrieved additional material through hand searches and personal contact with experts in the field. 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 RRs and ORs. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ).
Table 1.
GRADE evaluation of interventions for dengue fever or dengue shock sydrome in children
| Important outcomes | Symptom severity, mortality, adverse effects | ||||||||
| Number of 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 v colloids | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for delayed measurement of outcome |
| 1(383) | Symptom severity | Ringer's lactate v colloids (moderately severe shock) | 4 | 0 | 0 | 0 | 0 | High | |
| 1(129) | Symptom severity | Dextran v starch solutions (severe shock) | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 2 (172) | Symptom severity | Carbazochrome v placebo | 4 | –3 | –1 | –1 | 0 | Very low | Quality points deducted for sparse data, incomplete reporting of results, no intention-to-treat analysis, and methodological flaws. Consistency point deducted for conflicting results. Directness point deducted for baseline differences of population (uncertainty about duration of illness or age of participants) |
| at least 2 RCTs (at least 89 children) | Symptom severity | Corticosteroids v no treatment | 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 | Corticosteroids v placebo or no treatment | 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 | Intravenous immunoglobulin (IVIG) v no IVIG | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 1 (216) | Mortality | Intravenous immunoglobulin v placebo | 4 | 0 | 0 | 0 | 0 | High | |
| 1 (25) | Symptom severity | Recombinant activated factor VII (rFVIIa) | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
Type of evidence: 4 = RCT; 2 = ObservationalConsistency: similarity of results across studies Directness: generalisability of population or outcomes Effect size: based on relative risk or odds ratio
Glossary
- High-quality evidence
Further research is very unlikely to change our confidence in the estimate of effect.
- 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.
References
- 1.World Health Organization. Dengue hemorrhagic fever: diagnosis, treatment, prevention and control. Geneva: WHO 1997. [Google Scholar]
- 2.Pinheiro FP, Corber SJ. Global situation of dengue and dengue haemorrhagic fever, and its emergence in the Americas. World Health Stat Q 1997;50:161–168. [PubMed] [Google Scholar]
- 3.Gubler DJ. Dengue and dengue hemorrhagic fever. Clin Microbiol Rev 1998;11:480–494. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Guzman MG, Kouri G. Dengue: an update. Lancet Infect Dis 2002;2:33–42. [DOI] [PubMed] [Google Scholar]
- 5.Githeko AK, Lindsay SW, Confalonieri UE, et al. Climate change and vector-borne diseases: a regional analysis. Bull World Health Organ 2000;78:1136–1147. [PMC free article] [PubMed] [Google Scholar]
- 6.Cardosa MJ. Dengue haemorrhagic fever: questions of pathogenesis. Curr Opin Infect Dis 2000;13:471–475. [DOI] [PubMed] [Google Scholar]
- 7.Morens DM. Antibody-dependent enhancement of infection and the pathogenesis of viral disease. Clin Infect Dis 1994;19:500–512. [DOI] [PubMed] [Google Scholar]
- 8.Vaughn DW, Green S, Kalayanarooj S, et al. Dengue viremia titer, antibody response pattern, and virus serotype correlate with disease severity. J Infect Dis 2000;181:2–9. [DOI] [PubMed] [Google Scholar]
- 9.Rigau-Perez JG, Clark GG, Gubler DJ, et al. Dengue and dengue hemorrhagic fever. Lancet 1998;352:971–977. [DOI] [PubMed] [Google Scholar]
- 10.Dung NM, Day NPJ, Tam DTH, et al. Fluid replacement in dengue shock syndrome: a randomized, double-blind comparison of four intravenous-fluid regimens. Clin Infect Dis 1999;29:787–794. [DOI] [PubMed] [Google Scholar]
- 11.Ngo NT, Cao XT, Kneen R, et al. Acute management of dengue shock syndrome: a randomized double-blind comparison of 4 intravenous fluid regimens in the first hour. Clin Infect Dis 2001;32:204–213. [DOI] [PubMed] [Google Scholar]
- 12.Wills BA, Nguyen MD, Ha TL, et al. Comparison of three fluid solutions for resuscitation in dengue shock syndrome. N Engl J Med 2005;353:877–889. [DOI] [PubMed] [Google Scholar]
- 13.Halstead SB, O'Rourke EJ. Editorial response: resuscitation of patients with dengue hemorrhagic fever/dengue shock syndrome. Clin Infect Dis 1999;29:795–796. [DOI] [PubMed] [Google Scholar]
- 14.Tassniyom S, Vasanawathana S, Dhiensiri T, et al. Failure of carbazochrome sodium sulfonate (AC-17) to prevent dengue vascular permeability or shock: a randomized, controlled trial. J Pediatr 1997;131:525–528. [DOI] [PubMed] [Google Scholar]
- 15.Funahara Y, Sumarmo, Shirahata A, et al. Protection against marked plasma leakage in dengue haemorrhagic fever by infusion of carbazochrome sodium sulfonate (AC-17). Southeast Asian J Trop Med Public Health 1987;18:356–361. [PubMed] [Google Scholar]
- 16.Panpanich R, Sornchai P, Kanjanaratanakorn K. Corticosteroids for treating dengue shock syndrome. In: The Cochrane Library, Issue 2, 2008. Chichester, UK: John Wiley & Sons, Ltd. Search date 2006. [DOI] [PubMed] [Google Scholar]
- 17.Tassniyom S, Vasanawathana S, Chirawatkul A, et al. Failure of high-dose methylprednisolone in established dengue shock syndrome: a placebo-controlled, double-blind study. Pediatrics 1993;92:111–115. [PubMed] [Google Scholar]
- 18.Sumarmo, Talogo W, Asrin A, et al. Failure of hydrocortisone to affect outcome in dengue shock syndrome. Pediatrics 1982;69:45–49. [PubMed] [Google Scholar]
- 19.Min M, Tin U, Aye M, et al. Hydrocortisone in the management of dengue shock syndrome. Southeast Asian J Trop Med Public Health 1975;6:573–579. [PubMed] [Google Scholar]
- 20.Pongpanich B, Bhanchet P, Phanichyakarn P, et al. Studies on dengue hemorrhagic fever. Clinical study: an evaluation of steroids as a treatment. J Med Assoc Thai 1973;56:6–14. [PubMed] [Google Scholar]
- 21.Dimaano EM, Saito M, Honda S, et al. Lack of efficacy of high-dose intravenous immunoglobulin treatment of severe thrombocytopenia in patients with secondary dengue virus infection. Am J Trop Med Hygiene 2007;77:1135–1138. [PubMed] [Google Scholar]
- 22.Frias MV. The use of intravenous immunoglobulin in dengue shock syndrome: a randomized double-blind placebo-controlled trial [dissertation]. Manila, The Philippines: University of the Philippines College of Medicine 1999. [Google Scholar]
- 23.Chuansumrit A, Wangruangsatid S, Lektrakul Y, et al. Control of bleeding in children with Dengue hemorrhagic fever using recombinant activated factor VII: a randomized, double-blind, placebo-controlled study. Blood Coag Fibrinolysis 2005;16:549–555. [DOI] [PubMed] [Google Scholar]
- 24.Wills BA, Nguyen MD, Ha TL, et al. Comparison of three fluid solutions for resuscitation in dengue shock syndrome. N Engl J Med 2005;353:877–889. [DOI] [PubMed] [Google Scholar]