Dengue virus is an arbovirus transmitted to humans by two species of mosquito, Aedes aegypti and A. albopictus. The four serotypes of dengue virus can cause a wide range of symptoms from mild febrile illness to severe haemorrhagic fever, which leads to dengue shock syndrome. Dengue haemorrhagic fever is said to be present when patients have high fever for two to seven days, bleeding, enlargement of the liver, and insufficient circulation (Nimmanitya 1993). Bleeding usually occurs and frequently presents as tiny, scattered, red spots in the skin (petechiae). Bleeding from the nose, gums, and gastrointestinal tract is less common but may be severe. There are four grades dengue haemorrhagic fever according to the level of shock or bleeding: grades I and II are non-shock dengue haemorrhagic fever, and grades III and IV are cases with shock (dengue shock syndrome) (WHO 1997).
Dengue haemorrhagic fever was first recognized in South-East Asia in the 1950s when outbreaks occurred in Philippines, Thailand, and Vietnam. The incidence of dengue haemorrhagic fever has increased in several countries in Asia and is one of the leading causes of death in children (Thongcharoen 1993). It is currently estimated that the majority of the 100 million cases of dengue infection that occur annually are in South-East Asia (Kautner 1997). Dengue haemorrhagic fever is also endemic in some parts of the Americas. Twenty-five countries in the Americas reported 42,246 cases of dengue haemorrhagic fever and 582 deaths between 1981 and 1996 (Pinheiro 1997), and an epidemic occurred in Cuba in 1981. There are increasing numbers of imported cases of dengue infection among travellers returning from these endemic areas (Kautner 1997).
It is unclear how dengue infection causes bleeding and shock. Immune responses seem to play an important role in causing illness. Infection with one of the four serotypes of dengue virus provides lifelong immunity to that serotype. Secondary infection with another serotype of dengue virus can form a 'virus-antibody complex' by combining with existing antibody from previous dengue infection. The virus-antibody complex promotes the growth of the virus in mononuclear cells and activates the complement system (Halstead 1993). In another hypothesis, genetic changes in the virus genome increase viral replication, virulence, and epidemic potential of the dengue virus (Gubler 1998). Capillary damage and increased permeability of vessel walls cause plasma to flow into extravascular spaces and increase the blood concentration. A depletion of plasma volume can cause low blood pressure and lead to shock in severe cases. Bleeding in dengue haemorrhagic fever is related to platelet depletion (thrombocytopenia, ≤ 100,000 platelets/mm
The standard treatment of dengue shock syndrome is to immediately administer intravenous fluids to expand plasma volume. People are at particular risk of circulatory problems when their fever resolves. Plasma leakage is thought to be self limiting and rarely lasts longer than 48 hours, so clinicians prevent shock by replacing the plasma volume as soon as the haematocrit concentration starts to rise (Nimmanitya 1993). Clinicians give blood if patients are bleeding. There are no drugs available specifically for the treatment of dengue haemorrhagic fever. Although carbazochrome sodium sulfonate (AC-17) was tested in clinical trials because it is thought to be protective against vascular damage and decrease the severity of plasma leakage, the authors of one study concluded no benefit was shown (Tassniyom 1997).
Corticosteroids are potent anti-inflammatory agents that have a wide range of effects on immunological processes and have found use in a broad spectrum of diseases (Kehrl 1983). The use of corticosteroids in the management of dengue haemorrhagic fever and dengue shock syndrome is under debate. The World Health Organization does not mention corticosteroids in the treatment guidelines for dengue shock syndrome (WHO 1997). Observational studies in Thailand have shown a marked decline in case-mortality rate without any use of corticosteroids; this was attributed to both close observation of the patients for signs of shock during the critical period and early replacement of plasma loss (Cohen 1964; Nimmanitya 1978). Corticosteroids are used in some countries, particularly those in South-East Asia for managing dengue shock syndrome. They are thought to be effective for stabilizing capillary permeability and have been used in addition to fluid replacement (Sumarmo 1987). This systematic review examines the best available evidence on the effects of corticosteroids on death in dengue shock syndrome.
To compare corticosteroids with placebo or no corticosteroids for treating dengue shock syndrome.
Criteria for considering studies for this review
Types of studies
Randomized and quasi-randomized controlled trials.
Types of participants
People diagnosed with dengue shock syndrome, as defined by the trial authors.
Types of interventions
Corticosteroids (methylprednisolone, hydrocortisone, dexamethasone).
Placebo or no corticosteroids.
Types of outcome measures
- Time to regain normal blood pressure.
- Intravenous fluid requirement during the period of shock.
- Blood transfusion.
- Severe complications, including pulmonary oedema, renal failure, hepatic failure, pulmonary haemorrhage and convulsion.
- Days in hospital.
- Adverse events.
Search methods for identification of studies
We attempted to identify all relevant trials regardless of language or publication status (published, unpublished, in press, and in progress).
We searched the following databases using the search terms and strategy described in Appendix 1: Cochrane Infectious Diseases Group Specialized Register (August 2009); Cochrane Central Register of Controlled Trials (CENTRAL) published in The Cochrane Library (2009, Issue 2); MEDLINE (1966 to August 2009); EMBASE (1974 to August 2009); and LILACS (1982 to August 2009).
We contacted individual researchers working in the field for unpublished trials.
We also checked the reference lists of all studies identified by the above methods.
Data collection and analysis
Selection of studies
Two authors independently screened the results of the literature search for potentially relevant trials. We used an eligibility form to assess these trials for inclusion in the review; the reasons for excluding studies are in the 'Characteristics of excluded studies'.
Data extraction and management
We used data extraction forms to collect information on the participants, methods, interventions, and outcomes. The first two authors independently extracted data. Where there were differences, we referred to the original papers. We checked the data sources to avoid extracting data from multiple publications based on the same data set.
Assessment of risk of bias in included studies
Two authors independently assessed generation of allocation sequence and allocation concealment as adequate, inadequate, or unclear (Jüni 2001). We also described who was blinded, and assessed the inclusion of all randomized participants in the final analysis to be adequate if 90% or more.
We used Review Manager 5 for data analysis. We combined dichotomous data using risk ratio (RR) and combined continuous data using mean difference (MD), both with 95% confidence intervals (CI).
We assessed heterogeneity by visually examining the forest plots and by using the chi-squared test for heterogeneity with a 10% level of statistical significance. The I
Description of studies
Trial location and participants
Two trials were conducted in Thailand (Pongpanich 1973; Tassniyom 1993), one in Burma (now known as Myanmar) (Min 1975), and one in Indonesia (Sumarmo 1982). Participants were children aged less than 15 years with serologically confirmed dengue and shock.
Three trials compared intravenous hydrocortisone hemisuccinate with no corticosteroids or placebo (Pongpanich 1973; Min 1975; Sumarmo 1982), and one compared methyl prednisolone with placebo (Tassniyom 1993).
All four trials reported on death (Pongpanich 1973; Min 1975; Sumarmo 1982; Tassniyom 1993), two reported the number needing a blood transfusion (Pongpanich 1973; Tassniyom 1993), and one reported the duration of hospitalization (Tassniyom 1993).
Risk of bias in included studies
Also see Table 1 and the 'Characteristics of included studies'.
Generation of allocation sequence was adequate in one trial. No trials described allocation concealment, three trials used double blinding, and the same three trials were adequate for the number of randomized participants included in the analysis.
Effects of interventions
Death was an outcome in all four trials, but only three reported deaths (Min 1975; Sumarmo 1982; Tassniyom 1993). Overall no benefit of corticosteroids was demonstrated, but the number of participants in the analysis was small (284 participants, Analysis 1.1).
Days in hospital
Trials in people with a life-threatening illness are not easy to conduct, and the authors of these trials did their best to ensure an unbiased comparison. However, the trials were conducted some time ago and methods have become more advanced and more stringent. In the context of current standards, these trials have potential for bias, as allocation was not clearly concealed in any of them. Four trials were included in the review and the results showed no benefits of corticosteroids in reducing death in dengue shock syndrome.
Implications for practice
There is insufficient evidence to justify the use of corticosteroids in managing dengue shock syndrome. They should not be used in dengue shock syndrome outside the context of carefully conducted randomized controlled trials.
Implications for research
Large, randomized controlled trials that carefully conceal allocation and measure death as an outcome are required. Types, dose, and duration of corticosteroids should also be studied.
Ratana Panpanich developed the protocol for this review during the Fellowship Programme organized in May and June 2001 by the Cochrane Infectious Diseases Group. The UK Department for International Development (DFID) supported this Fellowship through the Effective Health Care Alliance Programme at the Liverpool School of Tropical Medicine.
This document is an output from a project funded by the DFID for the benefit of developing countries. The views expressed are not necessarily those of DFID.
Data and analyses
- Top of page
- Authors' conclusions
- Data and analyses
- What's new
- Contributions of authors
- Declarations of interest
- Sources of support
- Differences between protocol and review
- Index terms
Appendix 1. Search methods: detailed search strategies
Last assessed as up-to-date: 8 January 2006.
Protocol first published: Issue 1, 2002
Review first published: Issue 3, 2006
Contributions of authors
All authors contributed to the development of the review, extraction of the data, analysis, and interpretation of the results.
Declarations of interest
Sources of support
- Faculty of Medicine, Chiang Mai University, Thailand.
- Department for International Development, UK.
Differences between protocol and review
The intravenous fluid requirement during the period of shock and blood transfusion were added as secondary outcomes measures as they are important supportive treatments in both groups. The amounts of fluids and blood requirements should be compared if they reported.
Medical Subject Headings (MeSH)
MeSH check words