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Cochrane Database of Systematic Reviews

Corticosteroids for dengue infection (Review)

Zhang F, Kramer CV

Zhang F, Kramer CV.


Corticosteroids for dengue infection.
Cochrane Database of Systematic Reviews 2014, Issue 7. Art. No.: CD003488.
DOI: 10.1002/14651858.CD003488.pub3.

www.cochranelibrary.com

Corticosteroids for dengue infection (Review)


Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cochrane Trusted evidence.
Informed decisions.
Library Better health. Cochrane Database of Systematic Reviews

TABLE OF CONTENTS
HEADER......................................................................................................................................................................................................... 1
ABSTRACT..................................................................................................................................................................................................... 1
PLAIN LANGUAGE SUMMARY....................................................................................................................................................................... 2
SUMMARY OF FINDINGS.............................................................................................................................................................................. 3
BACKGROUND.............................................................................................................................................................................................. 7
OBJECTIVES.................................................................................................................................................................................................. 8
METHODS..................................................................................................................................................................................................... 8
RESULTS........................................................................................................................................................................................................ 9
Figure 1.................................................................................................................................................................................................. 10
Figure 2.................................................................................................................................................................................................. 12
DISCUSSION.................................................................................................................................................................................................. 14
AUTHORS' CONCLUSIONS........................................................................................................................................................................... 15
ACKNOWLEDGEMENTS................................................................................................................................................................................ 15
REFERENCES................................................................................................................................................................................................ 16
CHARACTERISTICS OF STUDIES.................................................................................................................................................................. 17
DATA AND ANALYSES.................................................................................................................................................................................... 26
Analysis 1.1. Comparison 1 Steroids versus placebo/no steroids in patients with dengue-related shock, Outcome 1 Death........ 27
Analysis 1.2. Comparison 1 Steroids versus placebo/no steroids in patients with dengue-related shock, Outcome 2 Blood 27
transfusion.............................................................................................................................................................................................
Analysis 1.3. Comparison 1 Steroids versus placebo/no steroids in patients with dengue-related shock, Outcome 3 28
Complications........................................................................................................................................................................................
Analysis 1.4. Comparison 1 Steroids versus placebo/no steroids in patients with dengue-related shock, Outcome 4 Days in 28
hospital..................................................................................................................................................................................................
Analysis 2.1. Comparison 2 Steroids versus placebo/no steroids in patients with dengue at an early stage, Outcome 1 30
Complications in dengue at an early stage.........................................................................................................................................
Analysis 2.2. Comparison 2 Steroids versus placebo/no steroids in patients with dengue at an early stage, Outcome 2 Platelet 32
count on days one to four....................................................................................................................................................................
Analysis 2.3. Comparison 2 Steroids versus placebo/no steroids in patients with dengue at an early stage, Outcome 3 33
Haematocrit on days one to four.........................................................................................................................................................
Analysis 2.4. Comparison 2 Steroids versus placebo/no steroids in patients with dengue at an early stage, Outcome 4 White 33
blood cell count on days one to four..................................................................................................................................................
Analysis 2.5. Comparison 2 Steroids versus placebo/no steroids in patients with dengue at an early stage, Outcome 5 Adverse 34
events in dengue at an early stage......................................................................................................................................................
Analysis 2.6. Comparison 2 Steroids versus placebo/no steroids in patients with dengue at an early stage, Outcome 6 Patients 34
with drug-related adverse events........................................................................................................................................................
Analysis 2.7. Comparison 2 Steroids versus placebo/no steroids in patients with dengue at an early stage, Outcome 7 Patients 35
with other reported events..................................................................................................................................................................
Analysis 2.8. Comparison 2 Steroids versus placebo/no steroids in patients with dengue at an early stage, Outcome 8 Patients 36
with adverse events low-dose steroids versus placebo.....................................................................................................................
Analysis 2.9. Comparison 2 Steroids versus placebo/no steroids in patients with dengue at an early stage, Outcome 9 Patients 36
with adverse events high-dose steroids versus placebo....................................................................................................................
Analysis 2.10. Comparison 2 Steroids versus placebo/no steroids in patients with dengue at an early stage, Outcome 10 Patients 37
with adverse events low-dose versus high-dose steroids..................................................................................................................
ADDITIONAL TABLES.................................................................................................................................................................................... 37
APPENDICES................................................................................................................................................................................................. 40
WHAT'S NEW................................................................................................................................................................................................. 41
HISTORY........................................................................................................................................................................................................ 41
CONTRIBUTIONS OF AUTHORS................................................................................................................................................................... 42
DECLARATIONS OF INTEREST..................................................................................................................................................................... 42
SOURCES OF SUPPORT............................................................................................................................................................................... 42
DIFFERENCES BETWEEN PROTOCOL AND REVIEW.................................................................................................................................... 42
INDEX TERMS............................................................................................................................................................................................... 42

Corticosteroids for dengue infection (Review) i


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[Intervention Review]

Corticosteroids for dengue infection

Fan Zhang1, Christine V Kramer2

1School of Public Health and Management, Chongqing Medical University, Chongqing, China. 2Cochrane Infectious Diseases Group,
Liverpool School of Tropical Medicine, Liverpool, UK

Contact address: Fan Zhang, School of Public Health and Management, Chongqing Medical University, No. 1, Yi Xue Yuan Road,
Chongqing, 400016, China. 13983782377@126.com.

Editorial group: Cochrane Infectious Diseases Group.


Publication status and date: Unchanged, published in Issue 11, 2016.

Citation: Zhang F, Kramer CV. Corticosteroids for dengue infection. Cochrane Database of Systematic Reviews 2014, Issue 7. Art. No.:
CD003488. DOI: 10.1002/14651858.CD003488.pub3.

Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT

Background
Dengue is a common and important mosquito-borne viral infection. In many low- and middle-income countries it is endemic and is an
important public health problem. Severe dengue is an important cause of death in children. There is no specific treatment for dengue, but
observational studies suggest corticosteroids may have a benefit in dengue-related shock, and some people believe corticosteroids may
prevent the progression to severe illness if given early in the course of the illness.

Objectives
To compare treatment of dengue with and without use of corticosteroids or placebo in relation to preventing shock-related death and
disease progression in children and adults.

Search methods
We searched the Cochrane Infectious Disease Group Centralized Register; CENTRAL; MEDLINE; EMBASE; and LILACS, up to 6 January 2014.
We screened reference lists and contacted the relevant study authors for additional information where required.

Selection criteria
Randomized controlled trials or quasi-randomized controlled trials comparing corticosteroids with placebo or no corticosteroids in
patients diagnosed with dengue-related shock, or patients in an early symptomatic state of dengue with positive serology.

Data collection and analysis


Two researchers independently screened eligibility of records, extracted data and assessed quality of the studies. We presented findings
in meta-analysis and summary of findings tables and evaluated the quality of evidence using GRADE.

Main results
We included eight studies enrolling 948 participants in this review.

Paitents with dengue-related shock

Four studies enrolled children younger than 15 years with dengue-related shock at hospitals in Southeast Asia and evaluated intravenous
corticosteroids. The trials did not detect an effect on death (four trials, 284 participants, very low quality evidence), the need for blood
transfusion (two trials, 89 participants, very low quality evidence), pulmonary haemorrhage (one trial, 63 participants, very low quality
evidence), convulsions (one trial, 63 participants, very low quality evidence), or duration of hospitalization (one trial, 63 participants, very

Corticosteroids for dengue infection (Review) 1


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low quality evidence). The body of evidence is too small to confidently prove or exclude clinically important effects. Furthermore, the trials
are more than 20 years old with several methodological limitations.

Patients with dengue at an early stage

Four studies enrolled 664 children and adults with dengue at an early stage of infection (without shock) in Columbia, India, Sri Lanka
and Vietnam. In these participants there were no evidence of effects of oral or intravenous corticosteroids on mortality (four trials, 664
participants, low quality evidence), or on the development of complications of severe dengue such as shock (two trials, 286 participants,
very low quality evidence), severe bleeding (two trials, 425 participants, very low quality evidence), severe thrombocytopaenia (one trial,
225 participants, very low quality evidence), ascites (one trial, 178 participants, very low quality evidence) and intensive care unit (ICU)
admissions (two trials, 286 participants, very low quality evidence).

Authors' conclusions
The evidence from trials using corticosteroids in dengue is inconclusive and the quality of evidence is low to very low. This applies to both
the use of corticosteroids in dengue-related shock and for dengue at an early stage. There is insufficient evidence to evaluate the effects of
corticosteroids in the treatment of early stage dengue fever and dengue-related shock outside of the context of a randomized controlled
trial.

15 April 2019

No update planned

Other

This is not a current research question

PLAIN LANGUAGE SUMMARY

Corticosteroids for treating dengue infection in children and adults

Dengue is a disease caused by a virus transmitted by mosquitoes, occurring in many resource-limited countries, and children are often
most severely affected. Most infected patients will recover with mild symptoms, but a few progress to severe dengue and may die. There
is no specific treatment for dengue, but some clinicians provide corticosteroids at an early stage to prevent progression to severe dengue
disease; and some treat patients with dengue-related shock with corticosteroids to improve survival. It is important to summarise the
effects of corticosteroids in dengue.

We conducted a search up to 6 January 2014 and included eight studies which enrolled 948 participants in total. Four studies of
corticosteroids in the treatment of dengue-related shock assessed if corticosteroids could improve survival, but these studies were small
and older than 20 years. The evidence we found is of very low quality and do not provide any reliable evidence for corticosteroids for treating
dengue-related shock. Four trials evaluated whether corticosteroids provided at an early stage of dengue could prevent development of
complications of severe dengue. These trials were more recent, but data were insufficient to be sure whether corticosteroids have an effect
on the course of the disease.

Corticosteroids for dengue infection (Review) 2


Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Corticosteroids for dengue infection (Review)
SUMMARY OF FINDINGS

Summary of findings for the main comparison. Corticosteroid for dengue-related shock

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Corticosteroid for dengue-related shock

Patient or population: Patients with dengue-related shock


Settings: Endemic settings
Intervention: Corticosteroid

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Outcome: Complications of severe dengue

Outcomes Illustrative comparative risks* (95% CI) Relative effect No of partici- Quality of the evidence Comments
(95% CI) pants (GRADE)
Assumed risk Corresponding risk (studies)

Control Corticosteroid

Death 21 per 100 15 per 100 RR 0.68 284 ⊕⊝⊝⊝


(9 to 24) (0.42 to 1.11) (4 studies) very low 1,2,3,4

Need for 24 per 100 26 per 100 RR 1.08 89 ⊕⊝⊝⊝


blood trans- (12 to 54) (0.52 to 2.24) (2 studies) very low 5,6,7,8
fusion

Pulmonary 3 per 100 3 per 100 RR 0.97 63 ⊕⊝⊝⊝


haemorrhage (0 to 48) (0.06 to 14.82) (1 study) very low 9,10,11

Convulsions 0 per 100 0 per 100 RR 6.79 63 ⊕⊝⊝⊝


(0 to 0) (0.36 to 126.24) (1 study) very low 9,10,11

Days in hos- The mean duration of hos- The mean duration of hos- 63 ⊕⊝⊝⊝

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pital pital stay in the control pital stay in the intervention (1 study) very low 9,10,11
group was group was
6 days 1.1 days higher
(1.83 lower to 4.03 higher)

*The basis for the assumed risk (eg the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed
risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence


High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
3
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Corticosteroids for dengue infection (Review)
Low quality: 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.
Very low quality: We are very uncertain about the estimate.

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1 Downgraded by 1 for serious risk of bias: Three out of four studies were at unclear risk of selection bias, as sequence generation and allocation concealment were not reported
in sufficient detail. Blinding was adequate in two out of four studies. The only study that was at low risk of bias did not find an effect.
2 No serious inconsistency: Statistical heterogeneity was low. Three out of four studies found no evidence of a benefit with corticosteroids. Only the oldest study which was at
unclear risk of bias suggested a benefit.
3 No serious indirectness: All trials were performed in children aged below 15 years in hospitals in Southeast Asia, and the data may not be easily generalizable to other populations
or settings. All diagnoses were confirmed by a laboratory test, and an intravenous corticosteroid was used in all studies. Not downgraded.

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4 Downgraded by 2 for very serious imprecision: The 95% CI is wide and includes a clinically important effect and no effect. The trials are too small to detect an effect. To confidently
detect a 25% relative reduction in mortality would require a sample size of more than 1700 participants.
5 Downgraded by 1 for serious risk of bias: Sequence generation, allocation concealment and blinding was only reported adequately in one of the two studies. This study at low
risk of bias did not find an effect.
6 No serious inconsistency. No statistical heterogeneity.
7 No serious indirectness: Both trials were conducted in children in referral hospitals in Thailand. They used viral and serologic diagnostic tests and a similar total dose of
intravenous corticosteroids. The data may not be easily generalizable to other populations or settings. Not downgraded.
8 Downgraded by 2 for very serious imprecision: The 95% CI of RR was wide and the trials too small to detect an effect. To confidently detect a 25% relative reduction in need
for transfusion would require a sample size of more than 1400 participants.
9 No serious risk of bias: The one trial in this comparison reported adequate sequence generation, blinding and allocation concealment.
10 Downgraded by 1 for serious indirectness: Only a single small study evaluated this outcome. Further studies in different patient groups are needed to have confidence in the
results.
11 Downgraded by 2 for very serious imprecision: The 95% CI of the RR was wide and the trials too small to detect an effect. To confidently detect a 25% relative reduction would
require a sample size of more than 10,000 participants.

Summary of findings 2. Corticosteroid for dengue at an early stage

Corticosteroid for dengue at an early stage

Patient or population: Patients with dengue infection at an early stage


Settings: Endemic settings
Intervention: Corticosteroids

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Outcome: Complications of dengue

Outcomes Illustrative comparative risks* (95% CI) Relative effect No of participants Quality of the evidence Comments
(95% CI) (studies) (GRADE)
Assumed risk Corresponding risk

Control Corticosteroid

Death - - - 664 ⊕⊕⊝⊝ No deaths oc-


(4 studies) low 1,2,3 curred
4
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Corticosteroids for dengue infection (Review)
Severe dengue: 7 per 100 9 per 100 RR 1.30 286 ⊕⊝⊝⊝
shock (3 to 23) (0.48 to 3.51) (2 studies) very low 4,5,6

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Severe dengue: 1 per 100 1 per 100 RR 1.51 425 ⊕⊝⊝⊝7,8,9,10 Kularatne
severe bleeding very low 2009 reported
(0 to 5) (0.24 to 9.43) (2 studies) that no bleed-
ing compli-
cations oc-
curred

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Severe thrombo- 3 per 100 4 per 100 RR 1.51 (CI (0.31 to 7.28) 225 ⊕⊝⊝⊝
cytopaenia 11 (1 study) very low 12,13,14
(1 to 19)

Ascitis 4 per 100 1 per 100 RR 0.12 178 ⊕⊝⊝⊝


(0 to 9) (0.01 to 2.13) (1 study) very low 12,15,16

ICU admission 8 per 100 8 per 100 RR 0.88 286 ⊕⊝⊝⊝


(8 to 106) (0.38 to 1.99) (2 studies) very low 4,5,6

*The basis for the assumed risk (eg the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed
risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence


High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: 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.
Very low quality: We are very uncertain about the estimate.

1 No serious risk of bias: Three out of four trials reported adequate random sequence generation, adequate allocation concealment and blinding of clinicians and participants.
Two out of four trials reported adequate blinding of outcome assessors. One of the trials was available as conference abstract only and we got relevant information by email

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with the author.
2 No serious indirectness: The studies were conducted in different settings in South Asia (India, Sri Lanka), Southeast Asia (Vietnam) and Latin America (Colombia) in both adults
and children.
3 Downgraded by 2 for very serious imprecision: No deaths were reported in either the intervention or placebo/no intervention group.
4 Downgraded by 1 for serious risk of bias: One study reported adequately on sequence generation, allocation concealment and blinding of participants, clinicians and outcome
assessors. Another study was an open-label trial, and did not describe allocation concealment.
5 Downgraded by 1 for serious indirectness: These studies were conducted in different settings in India and Vietnam, which may not be easily generalizable to a variety of settings.
6 Downgraded by 2 for very serious imprecision: One trial reported that results for this outcome did not show a statistically significant difference and might be underpowered to
detect an effect. Another trial reported no case of shock in either the treatment or control groups. The 95% CI of the RR was wide and the trials too small to detect an effect. To
confidently detect a 25% relative reduction would require a sample size of more than 8000 participants.
7 No serious risk of bias: The two trials that reported on this outcome both described adequate allocation concealment and blinding of clinicians and participants. The method
of sequence generation was not clear in one study.
5
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Corticosteroids for dengue infection (Review)
8 No serious inconsistency. No statistical heterogeneity.
9 Downgrade by 1 for serious indirectness: The two trials that reported on this outcome were conducted in Sri Lanka and Vietnam. The studies used different diagnostic criteria
for dengue and for the diagnosis of haemorrhage and gave different doses of Prednisolone.

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10Downgraded by 2 for very serious imprecision: Only four events were reported in the corticosteroid group, with only event in the placebo group. One of the two studies,
conducted in Sri Lanka, did not report any events. The 95% CI of the RR was wide and the trials too small to detect an effect. To confidently detect a 25% relative reduction would
require a sample size of more than 70,000 participants.
11 Severe thrombocytopaenia: platelet nadir < 10,000/μl.
12 No serious risk of bias: The one trial in this comparison reported adequate sequence generation, blinding and allocation concealment.
13Downgraded by 1 for serious indirectness: The one study reporting on this outcome was conducted in Vietnam, which may not be easily generalizable to a variety of settings.
14Downgraded by 2 for very serious imprecision: The single trial reporting on this outcome reported few events. The 95% CI of the RR was wide and the trials too small to detect

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an effect. To confidently detect a 25% relative reduction would require a sample size of more than 2000 participants.
15 Downgraded by 1 for serious indirectness: This single study from Colombia may not easily be generalizable to a variety of settings.
16Downgraded by 2 for very serious imprecision: The single trial that reported on this outcome reported few events. The 95% CI of the RR was wide and the trials too small to
detect an effect. To confidently detect a 25% relative reduction would require a sample size of more than 9000 participants.

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BACKGROUND Americas, Southeast Asia and the Western Pacific exceeded 2.3
million in 2010. Its incidence has "multiplied many times over
Description of the condition the last five decades at an alarming rate"(Rajapakse 2012). An
estimated 500,000 people with severe dengue, of which a large
Dengue is a viral infection that causes fever, malaise (general feeling
proportion are children, require hospitalization every year. About
of discomfort and illness) and is occasionally fatal. There are in total
2.5% of these patients die of the disease (WHO 2009, WHO 2012a).
four different strains of the dengue virus. The bite of the female
infected Aedes mosquito, most commonly Aedes aegypti, transmits The Southeast Asia and the Western Pacific regions carry more than
the virus to humans (WHO 2009; Simmons 2012). 75% (about 1.8 billion population) of the disease burden. These
two regions plus the Americas are the three most seriously affected
Onset of the illness is sudden after an incubation period of three
regions. Many tropical diseases are more common in rural areas,
to 14 days (average four to seven days). In the early phases of
but dengue infections are acquired mostly in urban and semi-urban
the illness people have non-specific flu-like symptoms, nausea
areas, which puts tourists at higher risk and is an important reason
and vomiting, and half of them have a rash. The course of
for its increasing endemicity (WHO 2009).
dengue is usually mild and people recover. However, sometimes
complications occur in the critical phase when fever resolves on the All age groups are affected, but infants and young children
third to seventh day of illness, usually on the fifth day (WHO 2009; are at greater risk of dengue-related shock which is proved by
Simmons 2012). epidemiological studies. The potential mechanism may explain
this. Further risk factors include female sex, high body-mass index
Before 2009, the WHO classified dengue fever (DF) and four
(BMI), infection with certain virus strains, or individual genetic
stages of dengue haemorrhagic fever (DHF) according to clinical
susceptibility (Greenfacts 2012; Simmons 2012; WHO 2012b).
manifestations as shock or bleeding. Grade I and II were termed
non-shock DHF while grade III and IV were defined as dengue shock Diagnosis
syndrome (DSS) (WHO 1997). This classification did not reliably
identify severely sick patients, therefore the WHO introduced a Clinicians diagnose severe dengue (including dengue-related
new classification in 2009. This new classification differentiates shock) on clinical grounds. Laboratory tests confirm the clinical
between dengue, an uncomplicated disease with full recovery; and diagnosis. Blood tests support diagnosis and guide management
severe dengue. In severe dengue, an effect of the infection on the (WHO 2009). Current diagnostic methods include the detection of
capillaries causes complications: the permeability of the capillaries virus (or virus isolation), viral nucleic acid and viral antigen, and the
increases and fluid leaks from the vessels into the tissue, causing a detection of dengue-specific antibodies in the blood.
fall in blood pressure and shock. The WHO defines severe disease
Management
as:
Currently there is no evidence-base for a specific drug for dengue.
• plasma leakage leading to shock or breathing difficulties, or Medical interventions remain supportive instead of curative.
both; Patients receive fluid transfusions when hospitalized. Platelets are
• severe bleeding; given when platelet counts drop too low. Severe anaemia in dengue
• severe organ impairment (WHO 2009). is treated with blood transfusions. For dengue-related shock ,
the WHO provides detailed recommendations for intravenous
Signs of dengue-related shock are a narrow pulse pressure of 20 fluid resuscitation (WHO 2009; Simmons 2012). Non-steroidal anti-
mmHg or less, and poor skin perfusion (Simmons 2012). Blood inflammatory drugs such as ibuprofen should be avoided as they
tests show increasing concentration of the blood and low levels of can worsen bleeding tendency.
platelets and protein. The mechanisms leading to plasma leakage
and the role of the immune system in the development of shock are Description of the intervention
unclear. Researchers suggest that the immune response can result
Corticosteroids are potent anti-inflammatory agents with multiple
in increased permeability of the capillaries. No animal models exist
effects on the immune system and a wide range of applications.
(WHO 2009; Simmons 2012).
In the twentieth century, some researchers conducted studies
Epidemiology on the effect of intravenous corticosteroids on dengue-related
shock. More recently, researchers began to investigate whether
Dengue is the most common vector born viral infection in humans intravenous or oral corticosteroids were effective in preventing
and the most rapidly spreading viral disease globally, and an disease progression from dengue at an early stage of infection
important public health problem in low- and middle-income to severe dengue (Kularatne 2009; Shashidhara 2013; Tam 2012;
countries in the tropics where most of the dengue infection Villar 2009). Currently, the WHO does not recommend the use of
happens The dispersal of the efficient mosquito vectors across corticosteroids either in severe dengue or in dengue at an early
much of the tropical and subtropical latitudes is crucial for the stage of infection (WHO 2009).
cause of public health problems. The primary vector has been
widely distributed across these tropics (Simmons 2012). And the How the intervention might work
dengue epidemics are closely related to the seasonal climatic
change and there are epidemics waves following each rainy season The mechanism in dengue resulting in plasma leakage is
(Rajapakse 2012). still unclear. Complications such as dengue-related shock are
occasionally reported during primary infection (the first time a
Over 40% of the world's population (about 2.5 billion) live in person is infected by a dengue virus), but are strongly associated
dengue-endemic areas, and about 50 to 100 million people are with secondary infection (the second time a person is infected,
infected with the dengue virus every year. Cases across the possibly by a different serotype of the dengue virus). This indicates
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an involvement of the immune system, and the mechanism is Types of interventions


mediated and enhanced by antibodies against the dengue virus
Intervention
(WHO 2009). Clinicians give corticosteroids when they think the
host immune response contributes to the disease process. In Intravenous or oral corticosteroids (methylprednisolone,
some areas, corticosteroids have been used for the treatment of hydrocortisone, dexamethasone or any other kind of corticosteroid
dengue-related shock or at an early stage of dengue infection. mentioned in the trial).
Observational studies have suggested corticosteroids may benefit
people with dengue-related shock (WHO 2009; Kularatne 2009; Tam Control
2012 ).
Placebo or no corticosteroids.
Clinicians have employed the anti-inflammatory effect of
corticosteroids for the treatment of shock caused by sepsis. Types of outcome measures
Patients with sepsis have elevated blood levels of pro- Primary outcomes
inflammatory cytokines for weeks after clinical resolution of
infection, during which shock may become manifest. Studies that • Death
have used lower doses of hydrocortisone (≤ 300 mg per day or
equivalent) for longer durations have reported earlier reversal of Secondary outcomes
shock and improved survival (Sprung 2008). A recent systematic • For patients with dengue-related shock, measures of severity
review demonstrated that corticosteroids had no clear benefit on including:
mortality in severe sepsis and septic shock (Annane 2009).
• Blood transfusion
However, recent trials have investigated corticosteroids for treating • Complications, such as pulmonary haemorrhage and
dengue at an early stage because researchers assumed that convulsion
corticosteroids might be effective in preventing complications • Duration of shock (hours)
when given early in the course of infection (Tam 2012). • Days in hospital or duration of hospitalization (days)
• Adverse events
Why it is important to do this review
• For patients with dengue at an early stage, measures of the onset
Dengue poses a relevant global public health problem in resource- of severe dengue including:
poor settings. It is important to evaluate effective treatment • Dengue-related shock
options to establish the best possible therapy, and to identify
• Severe bleeding
ineffective treatment options which consume limited resources and
might do harm. • Severe thrombocytopaenia
• Ascites
With the revision of the WHO classification in 2009, the case • Intensive care uni (ICU)) admission
definition of severe dengue has become broader(WHO 2009).
• Any bleeding
Therefore, all cases classified as Dengue shock syndrome according
to the previous, stricter WHO definition (WHO 1997) will also meet • Hospital admission (frequency of hospitalization)
the criteria for severe dengue of the WHO definition of 2009. • Platelet count
• Haematocrit
OBJECTIVES • White blood cell count
To compare treatment of dengue with and without use of Adverse events
corticosteroids or placebo with regards to prevention of shock-
related death and disease progression in children and adults. • Patients with serious adverse events
• Patients with any adverse events
1. To assess the effects of corticosteroids for treating patients with
dengue-related shock • Patients with drug-related adverse events
2. To assess the effects of corticosteroids in preventing severe • Patients with other reported events
dengue in patients with dengue at an early stage • Patients with adverse events (for different comparisons: low-
dose corticosteroids versus placebo; high-dose corticosteroids
METHODS versus placebo; low-dose versus high-dose corticosteroid)

Criteria for considering studies for this review Search methods for identification of studies
Types of studies We attempted to identify all relevant trials regardless of language
or publication status (published, unpublished, in press and in
Randomized and quasi-randomized controlled trials.
progress).
Types of participants
Electronic searches
Children and adults patients diagnosed with dengue (at an early
We searched the following databases up until 6 January 2014 using
stage and in patients with dengue-related shock).
the search terms and strategy described in Appendix 1: Cochrane
Infectious Diseases Group Specialized Register; the Cochrane
Central Register of Controlled Trials (CENTRAL), published in The
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Cochrane Library; MEDLINE(via Pubmed); EMBASE; LILACS. We Unit of analysis issues


also searched the metaRegister of Controlled Trials (mRCT) using
The unit of analysis in all included trials was individual participants.
"dengue" AND ("steroid* OR corticosteroid*") as search terms.
One of our included studies, Tam 2012 had multiple intervention
Searching other resources arms with 150 patients in each arm including 75 in high-dose group
and 75 in low-dose group and 75 in the placebo group. When we
We screened the reference lists of existing reviews and of all trials did data analysis, we treat the study as two comparisons: one
identified by the above mentioned searches. comparing high-dose (75) with placebo (37) while another one
comparing low-dose (75) with placebo (38). We proportionately
Data collection and analysis divided the placebo into two parts.
Selection of studies
Dealing with missing data
Two authors (Fan Zhang,FZ; Veronika Christine Kramer, VK)
Where no data was missing or unclear, we analyzed data
independently screened the titles and abstracts identified by
according to the intention-to-treat principle (ie all randomized
the above search strategy and retrieved full-text articles of
participants were analyzed in the groups to which they were
potentially relevant trials. For the identified full-text articles, we
originally assigned). Where there was a discrepancy between the
also independently used an eligibility form to decide on the final
number randomized and the number analyzed, we calculated and
list of included studies. We listed excluded studies with the reason
presented the percentage loss to follow-up for each intervention
for exclusion. We contacted trial authors for clarification if eligibility
group. We contacted trial authors for missing or unclear data.
was unclear. We resolved disagreements by discussion with Paul
Where we got no response from them, we carried out the complete-
Garner (PG) and David Sinclair (DS).
case analysis (ie only the available data was analyzed and the
Data extraction and management missing data ignored).

Two authors independently extracted data using a pre-specified, Assessment of heterogeneity


pre-piloted data extraction form. For each outcome we extracted,
We looked for statistical heterogeneity by inspecting the forest plots
where available, the number of participants randomized, the
for overlapping confidence intervals, applying the Chi2 test (P value
number of participants analyzed in each treatment group, the
< 0.10 considered to be statistically significant), and the I2 statistic
main methods, as well as detail about the interventions and
(I2 value of 50% used to denote moderate levels of heterogeneity).
outcomes. For dichotomous outcomes, we recorded the number
of participants experiencing the event and the number assessed in Assessment of reporting biases
each intervention group. For continuous outcomes, we extracted
arithmetic means and standard deviations for each intervention The number of trials per meta-analysis was insufficient to construct
group, together with the numbers assessed in each group. a funnel plot to assess publication bias.
Two authors independently extracted and cross-checked data to
minimize errors. We contacted the trial authors for clarification or Data synthesis
missing data where necessary. We analyzed participants with dengue-related shock and
participants with dengue at an early stage separately.
Assessment of risk of bias in included studies
For this review update, we applied the latest Cochrane One author (FZ) analyzed the data using Review Manager 5.2, and
Collaboration methods for assessing risk of bias in included studies where appropriate we combined studies using a fixed-effect model.
(Higgins 2011). FZ and VK independently assessed the risk of If we detected heterogeneity, but still considered it was clinically
bias for each trial. We followed the guidance to assess whether meaningful to combine studies, we used a random-effects model.
adequate steps had been taken to reduce the risk of bias across six
Subgroup analysis and investigation of heterogeneity
domains: sequence generation; allocation concealment; blinding
(of participants, personnel, and outcome assessors); incomplete The number of the trials was insufficient to carry out a meaningful
outcome data; selective reporting; and other sources of bias. We subgroup analysis. According to our protocol, we would consider
categorized the risk of bias as 'high', 'low', or 'unclear' as per the potential sources of heterogeneity and do possible subgroup
Cochrane Handbook for Systematic Reviews of Interventions (Higgins analysis, such as study design, study setting and location,
2011). Where our judgment was unclear, we attempted to contact patient characteristics,, and the intervention given (different drug
the trial authors for clarification. We resolved any disagreements by regimens).
discussion with PG or DS. We presented this information in a risk of
bias summary table and used it for our interpretation of results. We Sensitivity analysis
used the GRADE approach to assist our assessment of the quality of The number of the trials was insufficient to carry out a meaningful
evidence and to prepare of 'Summary of findings' tables. sensitivity analysis. We have planned to do the sensitivity analysis
with regarding to the risk of bias.
Measures of treatment effect
We calculated results using the risk ratio (RR) for dichotomous data, RESULTS
and the mean difference (MD) for continuous data. These effect
estimates were presented with 95% confidence intervals (CI). Description of studies
All eight of the included studies (948 participants in total) were
randomized controlled trials.

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For further detail refer to the tables Characteristics of included We conducted an update search with a broader scope in June 2013,
studies and Characteristics of excluded studies. and repeated this search in January 2014. We identified four new
studies which explored the effects of corticosteroids in an early
Results of the search stage of dengue infection rather than in dengue-related shock.
The previous review authors conducted the original search in Figure 1 shows the study flow diagram. We contacted authors
January 2006 and included four unique trials which assessed the of five studies which provided email addresses of the contact
effects of corticosteroids on dengue shock syndrome. An update author or we found from other methods, and the contact author of
search in August 2009 did not yield any new trials. three studies(Tam 2012, Villar 2009, Tassniyom 1993) replied and
provided additional information (see 'Characteristics of included
studies').

Figure 1. Study flow diagram.

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Included studies dexamethasone with a control group which received no treatment.


Kularatne 2009 compared intravenous dexamethasone with
Dengue-related shock
placebo. Tam 2012 compared oral prednisolone with placebo. Villar
Four randomized controlled trials (Min 1975; Pongpanich 1973; 2009 compared oral methylprednisolone with placebo.
Sumarmo 1982; Tassniyom 1993) including 284 participants met
the inclusion criteria (see 'Characteristics of included studies') The Shashidhara 2013 enrolled adults (aged above 18 years) only. Tam
participants enrolled were all children less than 15 years old. 2012 enrolled children aged between ten and 15 years. The other
two trials (Kularatne 2009; Villar 2009) recruited both adults and
All four included trials originated from Southeast Asia: two were children.
conducted in Thailand (Pongpanich 1973; Tassniyom 1993), one
in Myanmar (Min 1975), and one in Indonesia (Sumarmo 1982). Villar 2009 reported on the clinical outcomes death, ascites and
All studies were hospital-based. Tassniyom 1993 enrolled patients frequency of hospitalization. Tam 2012 reported on shock, shock-
across two hospitals while the other three trials had patients related complications and thrombocytopaenia. Shashidhara 2013
enrolled in one hospital each. reported on death, shock and shock-related complications and
platelet counts. Kularatne 2009 reported on laboratory parameters
Three trials compared intravenous hydrocortisone hemisuccinate (platelet count, haematocrit and white blood cell count).
with no intervention (Pongpanich 1973; Min 1975) or with
placebo (Sumarmo 1982), and one compared intravenous Three trials (Kularatne 2009; Tam 2012; Villar 2009) reported either
methylprednisolone with placebo (Tassniyom 1993). spontaneous haemorrhage, severe bleeding or any bleeding.

All four trials reported on death, two reported the number needing Two trials reported on adverse events (Tam 2012, Villar 2009).
a blood transfusion (Pongpanich 1973; Tassniyom 1993), and one Tam 2012 used prospective, active surveillance to monitor adverse
reported complications (pulmonary haemorrhage and convulsion) events in a double-blind study (Table 1). Villar 2009 monitored
and duration of hospitalisation (Tassniyom 1993). None of these adverse events prospectively, according to the trial protocol, but
studies reported adverse events as an outcome (Table 1). did not describe the method of data collection. Clinicians and
participants were blinded. The author stated in the trial protocol
One trial was funded by the WHO (Sumarmo 1982), one by the that events were reported to an independent committee as fatal
Rockefeller Foundation (Tassniyom 1993), and funding was not serious adverse effects, life-threatening or clinically significant
specified for the other two trials (Min 1975; Pongpanich 1973). adverse events (Table 1).

Dengue at an early stage One trial was funded by the Wellcome Trust (Tam 2012). Funding
was not specified for the other three trials (Kularatne 2009;
Four randomized controlled trials (Kularatne 2009; Shashidhara
Shashidhara 2013; Villar 2009).
2013; Tam 2012; Villar 2009) including 664 participants (children
and adults) met the inclusion criteria (see 'Characteristics of Excluded studies
included studies') for the review.
Four trials (Futrakul 1981; Futrakul 1987; Sumarmo 1975; Sumarmo
Among these four studies, two were conducted in South Asia(Sri 1987) detected by the search specifications were excluded from the
Lanka (Kularatne 2009) and India (Shashidhara 2013); one in review (see 'Characteristics of excluded studies').
Southeast Asia (Vietnam, Tam 2012), and the fourth in Colombia,
Latin America (Villar 2009). Risk of bias in included studies

Two trials used intravenous corticosteroids, and two evaluated See Figure 2 for a summary of the risk of bias assessment. Further
oral corticosteroids. Shashidhara 2013 compared intravenous details are presented in the Characteristics of included studies
tables.

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Figure 2. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

1) Dengue-related shock other three trials did not describe sequence generation in sufficient
detail to allow a judgment.
For dengue-related shock, sequence generation and allocation
concealment were adequate in one trial (Tassniyom1993) while the Blinding was adequate in two trials (Tassniyom 1993; Sumarmo
1982), and unclear in the two other trials. No loss to follow-up

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occurred in these four hospital-based trials. We found no evidence Days in hospital


of selective outcome reporting and identified no other sources of
Tassniyom 1993 reported an average stay of 7.3 days in hospital
bias.
in the corticosteroid group and 6.2 days in the placebo group,
2) Dengue at an early stage without statistically significant difference between two groups (63
participants, Analysis 1.4).
Sequence generation was adequate in three trials (Shashidhara
2013; Tam 2012; Villar 2009) while a fourth trial did not describe Adverse events
sequence generation in sufficient detail to allow a judgment
None of the studies reported on adverse event monitoring.
Kularatne 2009).
Other outcomes: duration of shock
Allocation concealment and blinding of participants and personnel
were adequate in three trials (Kularatne 2009; Tam 2012; Villar 2009) Data for outcomes we could not present as meta-analysis were
and inadequate in the fourth trial (Shashidhara 2013). Blinding of summarized in Table 2.
outcome assessment was adequate in two trials (Tam 2012; Villar
2009) and unclear in one trial (Kularatne 2009). The fourth trial was One out of two studies (Min 1975) reported a significantly shorter
described as an open-label study (Shashidhara 2013) duration of shock in the corticosteroid group than in the placebo
group, while the second study (Pongpanich 1973) found no
Villar 2009 clearly stated that they used the intention-to- difference. These studies were small (124 participants across two
treat principle and gave the number of participants originally trials). Another study (Sumarmo 1982) reported the number of
randomized into two groups. Shashidhara 2013 reported no loss to participants who recovered from shock within a certain time
follow-up. Tam 2012 reported a small loss of follow-up. Kularatne period after corticosteroid or placebo treatment, and differences
2009 was the only study with a high loss of follow-up which was between the two groups appeared small (97 participants, one
due to poor patient compliance in comparatively healthy children. study). Statistical significance was not reported.
Both studies (Kularatne 2009; Tam 2012) reported the number of
participants originally randomized. 2) Corticosteroids for treating dengue at an early stage
Death
Only one trial (Shashidhara 2013) did not report all the pre-
specified outcomes. No evidence of selective outcome reporting No deaths in either the treatment or control (placebo or
was detected in the other three trials (Kularatne 2009; Tam 2012; no treatment) group were reported in any of the trials (664
Villar 2009). participants, four trials, Analysis 2.1).

No other sources of bias were identified. Severe dengue: dengue-related shock

Effects of interventions Two trials (Shashidhara 2013; Tam 2012) reported no difference in
patient numbers developing dengue-related shock after preventive
See: Summary of findings for the main comparison treatment with corticosteroids when compared to placebo or no
Corticosteroid for dengue-related shock; Summary of findings 2 corticosteroid (286 participants, Analysis 2.1).
Corticosteroid for dengue at an early stage
One trial (Tam 2012) with three study arms detected no significant
1) Corticosteroids for treating dengue-related shock difference in the risk of dengue-related shock after low-dose
Death corticosteroids, high-dose corticosteroids or placebo. Eleven per
cent of participants in the high-dose corticosteroid group and 7%
Corticosteroid treatment in dengue-related shock does not reduce in each of the low-dose and placebo groups developed shock.
mortality significantly when compared to placebo (four trials, 284 Another study reported no case of shock occurred in either the
participants, I2=0%, Analysis 1.1). In Pongpanich 1973, no one corticosteroid or in the control group (Shashidhara 2013).
died either in the corticosteroid or in the placebo group. In Min
1975, treatment with corticosteroids significantly reduced the risk Severe dengue: severe bleeding
of death. In Sumarmo 1982 and Tassniyom 1993, corticosteroids Two trials reported that corticosteroids did not significantly reduce
showed no statistically significant benefit. the risk of bleeding complications when compared to placebo (425
Blood transfusion participants, Analysis 2.1).

There was no statistically significant difference between the groups Significant bleeding or bleeding complications were rare.
in the number of participants needing blood transfusion (two trials, Kularatne 2009 observed no bleeding complications in either the
89 participants, Analysis 1.2) (Pongpanich 1973; Tassniyom 1993). corticosteroid or placebo group. Tam 2012 detected four cases
(2.67%) of significant or clinical bleeding in the group receiving
Complications corticosteroids (one in high-dose and three in low-dose group).
Two patients had dengue-related shock, one developed gross
Tassniyom 1993 reported no statistically significant difference
haematuria, and one suffered isolated upper gastrointestinal
between the corticosteroids and placebo groups for pulmonary
bleeding. One case (1.33%) was detected in the placebo group.
haemorrhage and convulsions (63 participants, Analysis 1.3).

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Severe thrombocytopaenia White blood cell count on days one to four


Corticosteroids did not significantly reduce the incidence of Kularatne 2009 found a significantly lower white blood cell count
severe thrombocytopaenia when compared to placebo in the one in the corticosteroid group on day 1 (mean difference, 4.8 cells/
trial that reported this outcome (225 participants, Analysis 2.1). mcL for corticosteroid and 5.7 cells/mcL for placebo group) (200
Severe thrombocytopaenia occurred in 4% of participants in the participants, Analysis 2.4), but no significant difference between
corticosteroid group and in 1% in the placebo group. the groups was detected on days 2, 3 or 4.

Ascitis Patients with adverse events


One trial (Villar 2009) reported that corticosteroids did not reduce Villar 2009 recorded adverse events prospectively and reported
the risk to develop ascites (178 participants, Analysis 2.1). While no in the conference abstract that "no adverse or severe events"
one developed ascites in the corticosteroid group, four participants occurred.
(4.40%) presented with ascites in the control group. However,
the difference was not statistically significant (178 participants, Tam 2012 used prospective, active surveillance to monitor serious
Analysis 2.1) and the study was not powered to detect an effect. and any adverse events (Table 1).

Intensive care unit (ICU) admission Serious adverse events: There was no difference in the
number of people who had serious adverse events after high-
Two trials (Shashidhara 2013; Tam 2012) reported on ICU dose corticosteroids, low-dose corticosteroids or placebo (403
admissions (286 participants, Analysis 2.1). Shashidhara 2013 participants, Tam 2012, Analysis 2.5, Analysis 2.8, Analysis 2.9,
recorded no ICU admissions either in the corticosteroid or control Analysis 2.10).
group. Tam 2012 did not find a significant difference in ICU
admissions between study arms (8% in the low-dose group, 10% in Any adverse event: There was no significant difference in
both the high-dose and the placebo groups). participants who experienced any adverse events across treatment
groups. The proportion of participants with any adverse events
Any bleeding was high with 30% in both the high-dose corticosteroid and
Corticosteroids reduced the risk of any bleeding by 15% when placebo groups and 20% in the low-dose corticosteroid group (403
compared to the placebo (RR 0.85, 95% CI 0.72 to 0.99, 403 participants, Tam 2012, Analysis 2.5, Analysis 2.8, Analysis 2.9,
participants, two studies, Analysis 2.1 ). Definitions of "any Analysis 2.10).
bleeding" differed between the two studies: Tam 2012 found
Drug-related adverse events: Tam 2012 found no significant
that approximately 70% of patients across all intervention groups
difference in the number of patients with hyperglycaemia,
experienced some form of bleeding as minor skin bleedings
hypertension, pneumonia and upper respiratory tract infection
(petechiae), skin bruising or mild to moderate mucosal bleeding.
after corticosteroid treatment when compared to placebo. The
Villar 2009 defined bleeding as "spontaneous haemorrhage", and
study authors thought these diagnoses to be possibly drug-related
reported proportions of 36% (in the corticosteroid group) to 50%
(225 participants, Analysis 2.6). The study also reported three other
(in the placebo group) suffered bleeding. The study protocol
adverse events, which they deemed not related to the study drug.
(Villar 2009) specified gastrointestinal bleeding or oral bleeding,
Again, the study detected no significant difference between study
nosebleed, blood in the urine (haematuria), minor skin bleedings
arms (225 participants, Analysis 2.7).
(petechiae), bruising or purple skin as spontaneous bleeding
manifestations. DISCUSSION
Hospital admission
Summary of main results
Villar 2009 found that corticosteroids had no significant effect on
Dengue-related shock
the number of hospitalizations required (178 participants, Analysis
2.1). Ten percent of patients in the corticosteroid and 16% in the The four trials evaluating corticosteroids in children with dengue-
placebo group were hospitalized. The study was not powered to related shock were conducted before 1988 and had small
detect an effect. participant numbers a high risk of bias. The meta-analysis was
underpowered with very low quality evidence, and did not
Platelet count on days one to four demonstrate an effect on mortality (four studies, 284 participants),
The combined results of two studies (Shashidhara 2013, Kularatne the need for blood transfusion (two studies, 89 participants),
2009) showed no statistically significant difference in platelet pulmonary haemorrhage (one study, 63 participants), or
counts between corticosteroid and control group on the first, convulsions (one study, 63 participants).
second, third or fourth day (261 participants, Analysis 2.2). The
Dengue at an early stage
results was heterogenous on the second day.
Intravenous or oral corticosteroids in children and adults with
Haematocrit on days one to four dengue infection have not been shown to reduce the risk of death
The study(Kularatne 2009) showed no significant difference (four trials, 664 participants, low quality of evidence) or the risk to
between the groups on days one, two, three or four (200 develop complications of severe dengue, such as shock (two trials,
participants, one study, Analysis 2.3 ). 286 participants, very low quality of evidence), severe bleeding
(two trials, 403 participants, very low quality of evidence), severe
thrombocytopaenia (one trial, 225 participants, very low quality
of evidence), ascites (one trial, 178 participants, very low quality
Corticosteroids for dengue infection (Review) 14
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evidence) and ICU admissions (two trials, 286 participants, very low A study nested in the trial by Tam 2012 explored the effects of low-
quality of evidence). dose corticosteroids, high-dose corticosteroids and placebo on the
immune response of patients with dengue at an early stage (Nguyen
Only four trials were included in this part of the review, and many 2013). The study reported a limited effect of corticosteroids
of the outcomes were reported by one trial only. on patients' cytokine levels and immune modulation. This is
consistent with results of the clinical trial (Tam 2012) which
Overall completeness and applicability of evidence detected no significant clinical benefits after corticosteroids. The
Dengue-related shock authors concluded that "early prednisolone therapy has little
impact on the host immune response", even if the dose might be
For the trials evaluating corticosteroids in shock the data was "too little or too late".
limited, and confined to studies in children only. All trials were
conducted in Southeast Asia. These small trials were similar in The current WHO strategy focusses on early diagnosis of dengue
terms of location, setting, and types of participants. cases and on staff training for improved case management, but
also emphasises the importance of a greater evidence-base for
Dengue at an early stage interventions (WHO 2012c).
The body of evidence for corticosteroids in dengue at an early
stage is limited. We identified four small trials from Colombia, AUTHORS' CONCLUSIONS
India, Sri Lanka and Vietnam, which included both children and
Implications for practice
adults. They used different oral corticosteroids (prednisolone
and methylprednisolone) (Tam 2012; Villar 2009) or intravenous At present, there is insufficient evidence to know if routinely using
dexamethasone in different doses (Kularatne 2009, Shashidhara corticosteroids in treating dengue-related shock in children and
2013) and were conducted in different settings. Ten of our review's adults has an effect.
outcomes were reported by only one trial (Analysis 2.1-Analysis
2.10). It is therefore difficult to generalize the findings. There is also insufficient evidence to know if using corticosteroids
in treating dengue at an early stage influences the course of the
Quality of the evidence disease.
Dengue-related shock Implications for research
We found the quality of evidence to be very low for all outcomes At present, recommended treatment for severe dengue is restricted
of this comparison. The four trials were conducted more than 25 to supportive therapy. More research is needed to evaluate if drug
years ago from 1960s to 1980s. They preceded newer guidance therapies such as corticosteroids are effective and safe and should
for transparent reporting on sequence generation and allocation be recommended or not.
concealment, and have methodological limitations. For our risk of
bias assessment, please see Figure 2. These trials were conducted For corticosteroid use in people with dengue-related shock, it
in hospital settings with low loss to follow-up, and no evidence of would require a trial of probably more than 1672 people to identify
selective outcome reporting. The trials were also underpowered an effect on death (sufficient sample size, Table 3). Whether
and thus too small to reliably detect an effect in the outcomes that this is a priority for care depends on balancing other potentially
they measured. For an estimation for the sample sizes that would important interventions are worth testing for managing severe
be required per study and per meta-analysis please see Table 3. dengue infection.

Dengue at an early stage For people with symptomatic dengue early in the illness, large,
The quality of evidence for this comparison of the review was low rigorously conducted randomized controlled trials that measure
for the outcome death, and very low for dengue-related shock, death or other severe dengue-related complications as an outcome
ICU admission, severe bleeding, severe thrombocytopaenia and would be needed to justify the use of corticosteroids, but these
ascites. The four trials have lower risk of bias and were conducted would need to be even larger, with an estimate sample size of over
more recently between 2004 and 2011. One out of four trials 8000 people (Table 3).
reported high loss to follow-up. Nevertheless, they are seriously
ACKNOWLEDGEMENTS
underpowered (Table 3) and cannot be easily generalized to various
settings. This was our reason for downgrading the quality of We acknowledge Paul Garner and David Sinclair for their advice
evidence. and constructive comments on our review. We are grateful to all
the members of the Fellowship Programme run by the Cochrane
Agreements and disagreements with other studies or Infectious Diseases Group for their help. We also thank Ratana
reviews Panpanich, P Sornchai and Kittika Kanjanaratanakorn, the authors
The findings of a former systematic review (Panpanich 2010) and of the previous Cochrane review "Corticosteroids for treating
two other literature reviews (Rajapakse 2009, Rajapakse 2012) that dengue shock syndrome" which we have updated.
evaluated the effects of corticosteroids in dengue-related shock
The editorial base for the Cochrane Infectious Diseases Group is
are consistent with our findings. However, these reviews did not
funded by UKaid from the UK Government for the benefit of low-
address the effects of corticosteroids in dengue at an early stage
and middle-income countries.
infection.

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denguecontrol/9789241504034/en/. Geneva, (accessed 7
WHO 1997 February 2014).
World Health Organization. Dengue haemorrhagic fever:
diagnosis, treatment, prevention and control. 2nd Edition.
Geneva: World Health Organization, 1997. References to other published versions of this review
Panpanich 2010
WHO 2009
Panpanich R, Sornchai P, Kanjanaratanakorn K.
World Health Organization. Dengue guidelines for diagnosis,
Corticosteroids for treating dengue shock syndrome.
treatment, prevention and control. New. Geneva: World Health
Cochrane Database of Systematic Reviews 2010, Issue 2. [DOI:
Organization, 2009.
10.1002/14651858.CD003488]
WHO 2012a
World Health Organization. Dengue and severe dengue. Fact
Sheet[January 2012]. http://www.who.int/mediacentre/
factsheets/fs117/en/index.html (accessed 7 Feburary 2014).

CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID]

Kularatne 2009
Methods Study design: randomized controlled trial

Study dates: June 2004 to February 2006

Diagnostics: clinical, serological (haemagglutinin inhibiting antibody essay (HIA), IgM and IgG ELISA)

Participants Number of participants randomized: 200 enrolled (100 in corticosteroid group; 100 in placebo group)

Age: 12 to 65 years

Inclusion criteria: with acute, serologically confirmed dengue, without any concomitant illnesses

Exclusions: patients with evidence of bleeding and shock

Interventions 1. Dexamethasone: intravenous 4 mg as the initial dose and 2 mg every 8 hours thereafter for 24 hours

2. Placebo: intravenous isotonic saline

Outcomes 1. Platelet count

2. Haematocrit

3. White blood cell count (WBC)

4. Bleeding complications

Notes Location: Central Hospital, Peradeniya , Sri Lanka

Transmission: not specified

Funding: not specified

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Kularatne 2009 (Continued)

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- Unclear risk Quote: "randomly assigned patients", no more detail about sequence genera-
tion (selection bias) tion

Allocation concealment Low risk Quote: "using sealed envelop method"


(selection bias)

Blinding of participants Low risk Quote: "placebo group received intravenous isotonic saline identical in ap-
and personnel (perfor- pearance to the active drug according to the same regimen"
mance bias)
All outcomes

Blinding of outcome as- Unclear risk Not specified


sessment (detection bias)
All outcomes

Incomplete outcome data High risk High losses to follow-up on days 3 and 4 were reported
(attrition bias)
All outcomes Treatment group: day 1: 0, day 2: 7%, day 3: 24%, day 4: 54%

Control group: day 1: 0, day 2: 8%, day 3: 21%, day 4: 64%

Selective reporting (re- Low risk No evidence of selective reporting


porting bias)

Other bias Low risk No other bias identified

Min 1975
Methods Study design: randomized controlled trial

Study dates: February 1973 to February 1974

Diagnostics: clinical, "serologically proven"

Participants Number of participants randomized: 98 enrolled (48 in corticosteroid group; 50 in control group).

Age: not reported

Inclusion criteria: children diagnosed with dengue shock syndrome using serological confirmation

Exclusions: not specified

Interventions 1. Hydrocortisone hemisuccinate: single dose of 25 mg/kg intravenous on day 1, 15 mg/kg on day 2, 10
mg/kg on day 3

2. No medication (fluid replacement only)

Outcomes 1. Death

2. Duration of shock

Notes Location: Children's hospital, Rangoon, Burma (Myanmar)

Transmission: not specified

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Min 1975 (Continued)


Funding: not specified

Fluid replacement included normal saline, Ringer lactate solution, plasma, and blood products

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- Unclear risk Quote: "Randomly selected in 2 groups after carefully matching them by age
tion (selection bias) groups and sex", no detail about method of sequence generation

Allocation concealment Unclear risk Not specified


(selection bias)

Blinding of participants Unclear risk Quote: "Double blind"


and personnel (perfor-
mance bias) No placebo given
All outcomes

Blinding of outcome as- Unclear risk Quote: "Double blind"


sessment (detection bias)
All outcomes No placebo given

Incomplete outcome data Low risk No losses to follow-up were reported


(attrition bias)
All outcomes

Selective reporting (re- Low risk No evidence of selective reporting


porting bias)

Other bias Low risk No other bias identified

Pongpanich 1973
Methods Study design: randomized controlled trial

Study dates: 1969 to 1971

Diagnostics: clinical diagnosis and serological or virological. Haemagglutination inhibition (HI) test per-
formed on paired sera; positive result was a fourfold rise in titre or a fixed level at 1:640 or more.

Participants Number of participants: randomized: 26 enrolled (7 in corticosteroid group; 19 in control group)

Age: 6.6 to 9.5 years

Inclusion criteria: children diagnosed with dengue shock syndrome using serological confirmation

Exclusions: not specified

Interventions 1. Hydrocortisone hemisuccinate: intravenous 25 mg/kg/day; 5 mg/kg at start, rest given in divided
doses every four to six hours in addition to fluid replacement

2. No medication (fluid replacement only)

Outcomes 1. Death

2. Duration of shock

3. Number requiring fluid replacement


Corticosteroids for dengue infection (Review) 19
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Pongpanich 1973 (Continued)


4. Number needing blood transfusion

Notes Location: Ramathibodi Hospital, Bangkok, Thailand

Transmission: not specified

Funding: not specified

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- Unclear risk Quote: "A card was drawn at onset of shock to decide which treatment pro-
tion (selection bias) gram would be given", no more detail about sequence generation

Allocation concealment Unclear risk Not specified


(selection bias)

Blinding of participants Unclear risk Not specified


and personnel (perfor-
mance bias)
All outcomes

Blinding of outcome as- Unclear risk Not specified


sessment (detection bias)
All outcomes

Incomplete outcome data Low risk No losses to follow-up were reported


(attrition bias)
All outcomes

Selective reporting (re- Low risk No evidence of selective reporting


porting bias)

Other bias Low risk No other bias identified

Shashidhara 2013
Methods Study design: randomized controlled trial

Study dates: June 2010 to June 2011

Diagnostics: serological (IgM ELISA)

Participants Number of participants randomized: 61 enrolled (30 in corticosteroid group; 31 in control group)

Age: above 18 years

Inclusion criteria: aged above 18 years; serologically confirmed IgM ELISA, when platelet counts
dropped below 50,000/cumm during the acute stage of illness

Exclusions: patients with evidence of bleeding and shock; patients with HIV, autoimmune disease, con-
nective tissue disorders and vasculitis, ITP, malignancy during direct examination and clinical investi-
gations if necessary; patients with diabetes mellitus, hypertension, history of peptic ulcer, hypersensi-
tivity to corticosteroids, total leucocyte counts of more than 11,000/cumm

Interventions 1. Dexamethasone: intravenous 8 mg as the initial dose and 4 mg every 8 hours thereafter for 4 days (iv
fluids were given whenever necessary)

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Shashidhara 2013 (Continued)


2. Control: only intravenous fluids and antipyretics whenever necessary

Outcomes 1. Platelet count

2. Death

3. Number developing dengue-related shock

4. Number requiring transfusion

Notes Location: JSS Hospital Mysore, Karnataka, India (tertiary medical care centre)

Transmission: not specified

Funding: not specified

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- Low risk Quote: "They were allotted randomly by blocked randomisation by using a
tion (selection bias) fixed blocking method"

Allocation concealment Unclear risk Not specified


(selection bias)

Blinding of participants High risk Quote:"open label"


and personnel (perfor-
mance bias)
All outcomes

Blinding of outcome as- High risk Quote:"open label"


sessment (detection bias)
All outcomes

Incomplete outcome data Low risk No losses to follow-up were reported


(attrition bias)
All outcomes

Selective reporting (re- High risk Among all data recorded, only platelet counts was reported
porting bias)

Other bias Low risk No other bias identified

Sumarmo 1982
Methods Study design: randomized controlled trial

Study dates: February 1978 to May 1979

Diagnostics: clinical and serological or virological: Haemagluttinin Inhibition (HI) test on acute and con-
valescent paired sera, technique of Clarke and Casals. Virus isolation by mosquito inoculation, tech-
nique of Rose and Gubler for patients with a fourfold increase of the HI antibody titre or patients who
died.

Participants Number of participants: randomized: 97 enrolled (47 in corticosteroid group; 50 in placebo group)

Age: 0.9 to 10 years

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Sumarmo 1982 (Continued)


Inclusion criteria: children with serologically confirmed dengue shock syndrome

Exclusions: not specified

Interventions 1. Hydrocortisone hemisuccinate: 50 mg/kg, single intravenous dose in addition to fluid replacement

2. Placebo: sodium chloride 0.9% with same colour and turbidity

Outcomes 1. Death

2. Duration of shock

3. Requirement of fluid replacement (mL)

Notes Location: Dr Cipto Mangunkusumo Hospital, Jakarta, Indonesia

Transmission: not specified

Funding: WHO Project ICPRPD 001

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- Unclear risk Quote: "divided group using a simple random assignment method", no more
tion (selection bias) detail about the method of sequence generation

Allocation concealment Unclear risk Not specified


(selection bias)

Blinding of participants Low risk Quote: "Double blind" and "Placebo packaged in indistinguishable coded
and personnel (perfor- vials"
mance bias)
All outcomes

Blinding of outcome as- Unclear risk Not specified


sessment (detection bias)
All outcomes

Incomplete outcome data Low risk No losses to follow-up were reported


(attrition bias)
All outcomes

Selective reporting (re- Low risk No evidence of selective reporting


porting bias)

Other bias Low risk No other bias identified

Tam 2012
Methods Study design: randomized controlled trial

Study dates: August 2009 to January 2011

Diagnostics: virological diagnosis (rapid test for dengue non-structural protein NS1 silver strip)

Participants Number of participants: randomized: 225 enrolled (150 in corticosteroid group including 75 in high-
dose group and 75 in low-dose group; 75 in placebo group)

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Tam 2012 (Continued)


Inclusion criteria: children and young adults

Age: 5 to 20 years (enrolled participants were 10 to 15 years of age)

with clinically suspected dengue, supported by a positive antigen test for dengue, fever for ≤72 hours
and negative pregnancy test

Exclusions: those weighing < 20 kg, those with evidence for any dengue-related complications, symp-
toms suggesting another infectious disease, or a past history of serious illness or chronic disease in-
cluding psychiatric/behavioural problems, and those taking regular medications

Interventions 1. prednisolone: low-dose (0.5 mg/kg) orally once daily for three days

2. prednisolone: high-dose (2 mg/kg) orally once daily for three days

3. placebo: placebo group was additionally 1:1 randomized to low- or high-dose placebo

Outcomes 1. Number of complications: dengue shock syndrome; ICU admission; severe thrombocytopaenia; sig-
nificant bleeding; severe abdominal pain; increased liver enzymes

2. Number of adverse events: hyperglycaemia, hypertension, pneumonia, upper respiratory infection

Platelet nadir days 3 to 8, 109/L

Laboratory endpoints: maximum haematocrit at days 3 to 8; %haemoconcentration

Virological endpoints (not of interest for this review)

Area under the curve (AUC) log viraemia at days 3 to 6, log 10 copies/mL; time to undetectable vi-
raemia, number and % with undetectable viraemia; days from enrolment, median (interquartile range,
IQR) to undetectable viraemia; time to negative NS1: number with negative NS1 %; days from enrol-
ment, median (IQR) to negative NS1

Notes Location: Hospital for Tropical Diseases, Ho Chi Min City, Vietnam

Transmission: not specified

Funding: Wellcome Trust

Tam 2012 defined platelet nadir < 10,000/μl

L = SAE as severe thrombocytopaenia.

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- Low risk Quote: "block randomisation"


tion (selection bias)

Allocation concealment Low risk Quote: "All participants and study staff were blind to the treatment allocation"
(selection bias) and "did not blind the dose allocation, but the placebo group was additionally

1:1 randomized to low- or high-dose placebo to maintain blinding of the drug"

Blinding of participants Low risk Quote: "identical prednisolone and placebo were available", and "placebo
and personnel (perfor- group was additionally 1:1 randomized to low- or high-dose placebo to main-
mance bias) tain blinding of the drug". They were blind to intervention or placebo, but not
All outcomes to high or low dose.

Blinding of outcome as- Low risk Email correspondence with author: "The study staff were the outcome asses-
sessment (detection bias) sors and they were blind"

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Tam 2012 (Continued)


All outcomes

Incomplete outcome data Low risk Low losses to follow-up were reported
(attrition bias)
All outcomes

Selective reporting (re- Low risk No evidence of selective reporting


porting bias)

Other bias Low risk No other bias identified

Tassniyom 1993
Methods Study design: randomized controlled trial

Study dates: 1987 to 1988

Diagnostics: viral isolation, serological diagnosis: haemagglutinin inhibition (HI) test, ELISA for dengue
antibodies

Participants Number of participants: randomized: 63 enrolled (32 in corticosteroid group; 31 in placebo group)

Age: 3 to 14 years

Inclusion criteria: children diagnosed with dengue shock syndrome using World Health Organization
clinical criteria and serological confirmation

Exclusions: not specified

Interventions 1. Methylprednisolone (Solumedrol, Upjohn): single intravenous dose of 30 mg/kg in addition to fluid
replacement

2. Placebo: 5% dextrose in normal saline solution

Outcomes 1. Death

2. Number needing blood transfusion

3. Duration of hospitalization

4. Number getting complications (separate data for each complication)

Notes Location: Khon Kaen University Hospital, and Khon Kaen Provincial Hospital in Khon Kaen, Thailand

Transmission: not specified

Funding: Rockefeller Foundation (grant RF 87006#95)

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- Low risk Quote: "Block randomisation" and "Generation of allocation sequence: gener-
tion (selection bias) ated by statistician and running number put on drug package"

Allocation concealment Low risk Email correspondence with author: "By using sealed envelopes"
(selection bias)

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Tassniyom 1993 (Continued)

Blinding of participants Low risk Quote: "Double blind", "All specimens were identified only by code number"
and personnel (perfor- and "identical placebo"
mance bias)
All outcomes

Blinding of outcome as- Low risk Email reply from author: outcome assessors was blinded to the intervention,
sessment (detection bias) they "knew patients by code number" only
All outcomes

Incomplete outcome data Low risk No losses to follow-up were reported


(attrition bias)
All outcomes

Selective reporting (re- Low risk No evidence of selective reporting


porting bias)

Other bias Low risk No other bias identified

Villar 2009
Methods Study design: randomized controlled trial

Study dates: July 2006 to January 2009

Diagnostics: clinical diagnosis or immuno chromatography test

Participants Number of participants randomized: 189 enrolled (87 in corticosteroid group; 91 in placebo group)

Age: not stated

Inclusion criteria: fever over 48 hours but less than 120 hours, with clinical diagnosis of dengue or im-
muno chromatography test, and free of clinical signs of plasma leakage

Exclusion criteria: leukocytosis; evidence of plasma leakage, hypotension, or major bleeding and bruis-
ing, hematemesis, melena, rectal bleeding and purple; oral intolerance; women of reproductive age
with amenorrhoea than 4 weeks; cancer, HIV/AIDS or haematological disorders; breast-feeding patients
and those with a history of diseases; patients who have visited a malaria endemic area in the last 30
days

Interventions 1. Metylprednisolone: single oral dose 1.5 mg/kg

2. Placebo

Outcomes 1. Complications such as number developing spontaneous haemorrhages and ascites

2. Frequency of hospitalization

3. Adverse or severe events or mortality

Notes Location: Bucaramanga, Colombia

Transmission: not specified

Funding: not specified

Risk of bias

Bias Authors' judgement Support for judgement

Corticosteroids for dengue infection (Review) 25


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Villar 2009 (Continued)

Random sequence genera- Low risk Email correspondence with author: "generated in the computer 4 lists of 25
tion (selection bias) randomly selected blocks with replacement"

Allocation concealment Low risk Email correspondence with author: "lists of numbers will be generated by
(selection bias) project engineer, who will be the only person to know that each code contains
measures of treatment during the period of collection of information"

Blinding of participants Low risk Quote: "blinded for participants, care givers"
and personnel (perfor-
mance bias)
All outcomes

Blinding of outcome as- Low risk Quote: "blinded for outcome adjudicators"
sessment (detection bias)
All outcomes

Incomplete outcome data Low risk Low losses of follow-up were reported
(attrition bias)
All outcomes

Selective reporting (re- Low risk No evidence of selective reporting


porting bias)

Other bias Low risk No other bias identified

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Futrakul 1981 Not a randomized or quasi-randomized controlled trial

Futrakul 1987 Not a randomized or quasi-randomized controlled trial

Nguyen 2013 The clinical outcomes of this trial are reported in Tam 2012

Sumarmo 1975 Not a randomized or quasi-randomized controlled trial

Sumarmo 1987 Duplicate data with an included trial

DATA AND ANALYSES

Comparison 1. Steroids versus placebo/no steroids in patients with dengue-related shock

Outcome or subgroup title No. of No. of Statistical method Effect size


studies partici-
pants

1 Death 4 284 Risk Ratio (M-H, Fixed, 95% CI) 0.68 [0.42, 1.11]

2 Blood transfusion 2 89 Risk Ratio (M-H, Fixed, 95% CI) 1.08 [0.52, 2.24]

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Outcome or subgroup title No. of No. of Statistical method Effect size


studies partici-
pants

3 Complications 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected

3.1 Pulmonary haemorrhage 1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

3.2 Convulsions 1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

4 Days in hospital 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only

Analysis 1.1. Comparison 1 Steroids versus placebo/no steroids


in patients with dengue-related shock, Outcome 1 Death.
Study or subgroup Corticosteroid Placebo or Risk Ratio Weight Risk Ratio
no steroid
n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI
Min 1975 9/48 19/50 59.28% 0.49[0.25,0.98]
Pongpanich 1973 0/7 0/19 Not estimable
Sumarmo 1982 8/47 9/50 27.78% 0.95[0.4,2.25]
Tassniyom 1993 4/32 4/31 12.94% 0.97[0.27,3.54]

Total (95% CI) 134 150 100% 0.68[0.42,1.11]


Total events: 21 (Corticosteroid), 32 (Placebo or no steroid)
Heterogeneity: Tau2=0; Chi2=1.68, df=2(P=0.43); I2=0%
Test for overall effect: Z=1.54(P=0.12)

Favours steroid 0.001 0.1 1 10 1000 Favours no steroid

Analysis 1.2. Comparison 1 Steroids versus placebo/no steroids in


patients with dengue-related shock, Outcome 2 Blood transfusion.
Study or subgroup Corticosteroid Placebo or Risk Ratio Weight Risk Ratio
no steroid
n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI
Pongpanich 1973 0/7 4/19 24.04% 0.28[0.02,4.59]
Tassniyom 1993 11/32 8/31 75.96% 1.33[0.62,2.86]

Total (95% CI) 39 50 100% 1.08[0.52,2.24]


Total events: 11 (Corticosteroid), 12 (Placebo or no steroid)
Heterogeneity: Tau2=0; Chi2=1.19, df=1(P=0.28); I2=16.05%
Test for overall effect: Z=0.2(P=0.84)

Favours steroid 0.001 0.1 1 10 1000 Favours no steroid

Corticosteroids for dengue infection (Review) 27


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Analysis 1.3. Comparison 1 Steroids versus placebo/no steroids


in patients with dengue-related shock, Outcome 3 Complications.
Study or subgroup Corticosteroid Placebo Risk Ratio Risk Ratio
n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI
1.3.1 Pulmonary haemorrhage
Tassniyom 1993 1/32 1/31 0.97[0.06,14.82]

1.3.2 Convulsions
Tassniyom 1993 3/32 0/31 6.79[0.36,126.24]

Favours steroid 0.01 0.1 1 10 100 Favours placebo

Analysis 1.4. Comparison 1 Steroids versus placebo/no steroids in


patients with dengue-related shock, Outcome 4 Days in hospital.
Study or subgroup Favours steroid Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) Fixed, 95% CI Fixed, 95% CI
Tassniyom 1993 32 7.3 (7.5) 31 6.2 (3.9) 0% 1.1[-1.83,4.03]

Favours steroid -50 -25 0 25 50 Favours placebo

Comparison 2. Steroids versus placebo/no steroids in patients with dengue at an early stage

Outcome or subgroup title No. of No. of Statistical method Effect size


studies partici-
pants

1 Complications in dengue at an early 4 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
stage

1.1 Death 4 664 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

1.2 Severe dengue: dengue-related shock 2 286 Risk Ratio (M-H, Fixed, 95% CI) 1.30 [0.48, 3.51]

1.3 Severe dengue: severe bleeding 2 425 Risk Ratio (M-H, Fixed, 95% CI) 1.50 [0.24, 9.30]

1.4 Severe thrombocytopaenia 1 225 Risk Ratio (M-H, Fixed, 95% CI) 1.51 [0.31, 7.28]

1.5 Ascites 1 178 Risk Ratio (M-H, Fixed, 95% CI) 0.12 [0.01, 2.13]

1.6 ICU admission 2 286 Risk Ratio (M-H, Fixed, 95% CI) 0.88 [0.38, 1.99]

1.7 Any bleeding 2 403 Risk Ratio (M-H, Fixed, 95% CI) 0.84 [0.72, 0.98]

1.8 Hospital admission 1 179 Risk Ratio (M-H, Fixed, 95% CI) 0.63 [0.29, 1.37]

2 Platelet count on days one to four 2 Mean Difference (IV, Fixed, 95% Subtotals only
CI)

2.1 Day 1 2 261 Mean Difference (IV, Fixed, 95% -0.88 [-3.55, 1.80]
CI)

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Outcome or subgroup title No. of No. of Statistical method Effect size


studies partici-
pants

2.2 Day 2 2 246 Mean Difference (IV, Fixed, 95% 0.35 [-5.02, 5.71]
CI)

2.3 Day 3 2 216 Mean Difference (IV, Fixed, 95% 2.58 [-5.81, 10.96]
CI)

2.4 Day 4 2 143 Mean Difference (IV, Fixed, 95% -6.97 [-20.69, 6.75]
CI)

3 Haematocrit on days one to four 1 Mean Difference (IV, Fixed, 95% Subtotals only
CI)

3.1 Day 1 1 200 Mean Difference (IV, Fixed, 95% 0.0 [-1.54, 1.54]
CI)

3.2 Day 2 1 185 Mean Difference (IV, Fixed, 95% 0.90 [-0.70, 2.50]
CI)

3.3 Day 3 1 155 Mean Difference (IV, Fixed, 95% -0.60 [-2.29, 1.09]
CI)

3.4 Day 4 1 82 Mean Difference (IV, Fixed, 95% 2.0 [-0.16, 4.16]
CI)

4 White blood cell count on days one to 1 Mean Difference (IV, Fixed, 95% Subtotals only
four CI)

4.1 Day 1 1 200 Mean Difference (IV, Fixed, 95% -0.90 [-1.64, -0.16]
CI)

4.2 Day 2 1 185 Mean Difference (IV, Fixed, 95% 0.0 [-0.86, 0.86]
CI)

4.3 Day 3 1 155 Mean Difference (IV, Fixed, 95% -0.5 [-1.49, 0.49]
CI)

4.4 Day 4 1 81 Mean Difference (IV, Fixed, 95% -0.29 [-1.68, 1.10]
CI)

5 Adverse events in dengue at an early 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
stage

5.1 Patients with serious adverse events 2 403 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.50, 2.03]

5.2 Patients with any adverse events 2 403 Risk Ratio (M-H, Fixed, 95% CI) 0.89 [0.57, 1.38]

6 Patients with drug-related adverse 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
events

6.1 Hyperglycaemia 1 225 Risk Ratio (M-H, Fixed, 95% CI) 2.33 [0.69, 7.90]

6.2 Hypertension 1 225 Risk Ratio (M-H, Fixed, 95% CI) 0.17 [0.01, 4.10]

6.3 Pneumonia 1 225 Risk Ratio (M-H, Fixed, 95% CI) 0.51 [0.03, 7.88]

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Outcome or subgroup title No. of No. of Statistical method Effect size


studies partici-
pants

6.4 Upper respiratory infection 1 225 Risk Ratio (M-H, Fixed, 95% CI) 1.51 [0.24, 9.41]

7 Patients with other reported events 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only

7.1 Urticaria 1 225 Risk Ratio (M-H, Fixed, 95% CI) 0.17 [0.01, 4.10]

7.2 Febrile convulsion 1 225 Risk Ratio (M-H, Fixed, 95% CI) 1.5 [0.06, 35.96]

7.3 Diarrhoea 1 225 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

8 Patients with adverse events low-dose 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
steroids versus placebo

8.1 Patients with serious adverse events 1 150 Risk Ratio (M-H, Fixed, 95% CI) 0.6 [0.23, 1.57]

8.2 Patients with any adverse events 1 150 Risk Ratio (M-H, Fixed, 95% CI) 0.73 [0.42, 1.27]

9 Patients with adverse events high-dose 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
steroids versus placebo

9.1 Patients with serious adverse events 1 150 Risk Ratio (M-H, Fixed, 95% CI) 1.4 [0.66, 2.95]

9.2 Patients with any adverse events 1 150 Risk Ratio (M-H, Fixed, 95% CI) 1.05 [0.64, 1.70]

10 Patients with adverse events low-dose 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
versus high-dose steroids

10.1 Patients with any serious adverse 1 150 Risk Ratio (M-H, Fixed, 95% CI) 0.43 [0.17, 1.06]
events

10.2 Patients with any adverse events 1 150 Risk Ratio (M-H, Fixed, 95% CI) 0.70 [0.40, 1.21]

Analysis 2.1. Comparison 2 Steroids versus placebo/no steroids in patients with


dengue at an early stage, Outcome 1 Complications in dengue at an early stage.
Study or subgroup Corticosteroids Placebo or Risk Ratio Weight Risk Ratio
no steroids
n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI
2.1.1 Death
Kularatne 2009 0/100 0/100 Not estimable
Shashidhara 2013 0/30 0/31 Not estimable
Tam 2012 0/75 0/37 Not estimable
Tam 2012 0/75 0/38 Not estimable
Villar 2009 0/87 0/91 Not estimable
Subtotal (95% CI) 367 297 Not estimable
Total events: 0 (Corticosteroids), 0 (Placebo or no steroids)
Heterogeneity: Not applicable
Test for overall effect: Not applicable

Favours steroids 0.005 0.1 1 10 200 Favours placebo/control

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Study or subgroup Corticosteroids Placebo or Risk Ratio Weight Risk Ratio


no steroids
n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI
2.1.2 Severe dengue: dengue-related shock
Shashidhara 2013 0/30 0/31 Not estimable
Tam 2012 5/75 2/37 40.21% 1.23[0.25,6.06]
Tam 2012 8/75 3/38 59.79% 1.35[0.38,4.8]
Subtotal (95% CI) 180 106 100% 1.3[0.48,3.51]
Total events: 13 (Corticosteroids), 5 (Placebo or no steroids)
Heterogeneity: Tau2=0; Chi2=0.01, df=1(P=0.93); I2=0%
Test for overall effect: Z=0.52(P=0.6)

2.1.3 Severe dengue: severe bleeding


Kularatne 2009 0/100 0/100 Not estimable
Tam 2012 3/75 1/37 66.96% 1.48[0.16,13.75]
Tam 2012 1/75 0/38 33.04% 1.54[0.06,36.92]
Subtotal (95% CI) 250 175 100% 1.5[0.24,9.3]
Total events: 4 (Corticosteroids), 1 (Placebo or no steroids)
Heterogeneity: Tau2=0; Chi2=0, df=1(P=0.98); I2=0%
Test for overall effect: Z=0.44(P=0.66)

2.1.4 Severe thrombocytopaenia


Tam 2012 1/75 1/37 50.22% 0.49[0.03,7.67]
Tam 2012 5/75 1/38 49.78% 2.53[0.31,20.92]
Subtotal (95% CI) 150 75 100% 1.51[0.31,7.28]
Total events: 6 (Corticosteroids), 2 (Placebo or no steroids)
Heterogeneity: Tau2=0; Chi2=0.87, df=1(P=0.35); I2=0%
Test for overall effect: Z=0.51(P=0.61)

2.1.5 Ascites
Villar 2009 0/87 4/91 100% 0.12[0.01,2.13]
Subtotal (95% CI) 87 91 100% 0.12[0.01,2.13]
Total events: 0 (Corticosteroids), 4 (Placebo or no steroids)
Heterogeneity: Not applicable
Test for overall effect: Z=1.45(P=0.15)

2.1.6 ICU admission


Shashidhara 2013 0/30 0/31 Not estimable
Tam 2012 6/75 4/37 50.22% 0.74[0.22,2.46]
Tam 2012 8/75 4/38 49.78% 1.01[0.33,3.15]
Subtotal (95% CI) 180 106 100% 0.88[0.38,1.99]
Total events: 14 (Corticosteroids), 8 (Placebo or no steroids)
Heterogeneity: Tau2=0; Chi2=0.14, df=1(P=0.71); I2=0%
Test for overall effect: Z=0.32(P=0.75)

2.1.7 Any bleeding


Tam 2012 54/75 29/37 31.51% 0.92[0.74,1.15]
Tam 2012 52/75 29/38 31.23% 0.91[0.72,1.15]
Villar 2009 32/87 47/91 37.27% 0.71[0.51,1]
Subtotal (95% CI) 237 166 100% 0.84[0.72,0.98]
Total events: 138 (Corticosteroids), 105 (Placebo or no steroids)
Heterogeneity: Tau2=0; Chi2=2, df=2(P=0.37); I2=0.18%
Test for overall effect: Z=2.2(P=0.03)

Favours steroids 0.005 0.1 1 10 200 Favours placebo/control

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Study or subgroup Corticosteroids Placebo or Risk Ratio Weight Risk Ratio


no steroids
n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI
2.1.8 Hospital admission
Villar 2009 9/87 15/92 100% 0.63[0.29,1.37]
Subtotal (95% CI) 87 92 100% 0.63[0.29,1.37]
Total events: 9 (Corticosteroids), 15 (Placebo or no steroids)
Heterogeneity: Not applicable
Test for overall effect: Z=1.15(P=0.25)

Favours steroids 0.005 0.1 1 10 200 Favours placebo/control

Analysis 2.2. Comparison 2 Steroids versus placebo/no steroids in patients


with dengue at an early stage, Outcome 2 Platelet count on days one to four.
Study or subgroup corticosteroids placebo or Mean Difference Weight Mean Difference
no steroids
N Mean(SD) N Mean(SD) Fixed, 95% CI Fixed, 95% CI
2.2.1 Day 1
Shashidhara 2013 30 29.9 (14.2) 31 32.2 (12) 16.38% -2.3[-8.91,4.31]
Kularatne 2009 100 34.8 (10.7) 100 35.4 (10.4) 83.62% -0.6[-3.52,2.32]
Subtotal *** 130 131 100% -0.88[-3.55,1.8]
Heterogeneity: Tau2=0; Chi2=0.21, df=1(P=0.64); I2=0%
Test for overall effect: Z=0.64(P=0.52)

2.2.2 Day 2
Shashidhara 2013 30 44.2 (21.1) 31 56.7 (23.8) 22.61% -12.5[-23.78,-1.22]
Kularatne 2009 92 47.2 (21.4) 93 43.1 (20.9) 77.39% 4.1[-2,10.2]
Subtotal *** 122 124 100% 0.35[-5.02,5.71]
Heterogeneity: Tau2=0; Chi2=6.44, df=1(P=0.01); I2=84.47%
Test for overall effect: Z=0.13(P=0.9)

2.2.3 Day 3
Shashidhara 2013 30 74.1 (29.7) 31 78.5 (35) 26.56% -4.4[-20.67,11.87]
Kularatne 2009 79 64.1 (30.3) 76 59 (31.8) 73.44% 5.1[-4.69,14.89]
Subtotal *** 109 107 100% 2.58[-5.81,10.96]
Heterogeneity: Tau2=0; Chi2=0.96, df=1(P=0.33); I2=0%
Test for overall effect: Z=0.6(P=0.55)

2.2.4 Day 4
Shashidhara 2013 30 116.4 (43.9) 31 125.6 (41) 41.36% -9.2[-30.53,12.13]
Kularatne 2009 36 72.4 (44.4) 46 77.8 (36.4) 58.64% -5.4[-23.32,12.52]
Subtotal *** 66 77 100% -6.97[-20.69,6.75]
Heterogeneity: Tau2=0; Chi2=0.07, df=1(P=0.79); I2=0%
Test for overall effect: Z=1(P=0.32)
Test for subgroup differences: Chi2=1.54, df=1 (P=0.67), I2=0%

Favour corticosteroids -20 -10 0 10 20 Favours placebo

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Analysis 2.3. Comparison 2 Steroids versus placebo/no steroids in patients


with dengue at an early stage, Outcome 3 Haematocrit on days one to four.
Study or subgroup corticosteroids placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) Fixed, 95% CI Fixed, 95% CI
2.3.1 Day 1
Kularatne 2009 100 40.6 (5.5) 100 40.6 (5.6) 100% 0[-1.54,1.54]
Subtotal *** 100 100 100% 0[-1.54,1.54]
Heterogeneity: Not applicable
Test for overall effect: Not applicable

2.3.2 Day 2
Kularatne 2009 92 40.4 (5.2) 93 39.5 (5.9) 100% 0.9[-0.7,2.5]
Subtotal *** 92 93 100% 0.9[-0.7,2.5]
Heterogeneity: Not applicable
Test for overall effect: Z=1.1(P=0.27)

2.3.3 Day 3
Kularatne 2009 79 38.3 (4.9) 76 38.9 (5.8) 100% -0.6[-2.29,1.09]
Subtotal *** 79 76 100% -0.6[-2.29,1.09]
Heterogeneity: Not applicable
Test for overall effect: Z=0.69(P=0.49)

2.3.4 Day 4
Kularatne 2009 36 39.2 (4.5) 46 37.2 (5.5) 100% 2[-0.16,4.16]
Subtotal *** 36 46 100% 2[-0.16,4.16]
Heterogeneity: Not applicable
Test for overall effect: Z=1.81(P=0.07)
Test for subgroup differences: Chi2=4.07, df=1 (P=0.25), I2=26.3%

Favour corticosteroids -10 -5 0 5 10 Favours placebo

Analysis 2.4. Comparison 2 Steroids versus placebo/no steroids in patients with


dengue at an early stage, Outcome 4 White blood cell count on days one to four.
Study or subgroup corticosteroids placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) Fixed, 95% CI Fixed, 95% CI
2.4.1 Day 1
Kularatne 2009 100 4.8 (2.4) 100 5.7 (2.9) 100% -0.9[-1.64,-0.16]
Subtotal *** 100 100 100% -0.9[-1.64,-0.16]
Heterogeneity: Not applicable
Test for overall effect: Z=2.39(P=0.02)

2.4.2 Day 2
Kularatne 2009 92 5.9 (2.6) 93 5.9 (3.3) 100% 0[-0.86,0.86]
Subtotal *** 92 93 100% 0[-0.86,0.86]
Heterogeneity: Not applicable
Test for overall effect: Not applicable

2.4.3 Day 3
Kularatne 2009 79 6.6 (3) 76 7.1 (3.3) 100% -0.5[-1.49,0.49]
Subtotal *** 79 76 100% -0.5[-1.49,0.49]
Heterogeneity: Not applicable

Favour corticosteroids -10 -5 0 5 10 Favours placebo

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Study or subgroup corticosteroids placebo Mean Difference Weight Mean Difference


N Mean(SD) N Mean(SD) Fixed, 95% CI Fixed, 95% CI
Test for overall effect: Z=0.99(P=0.32)

2.4.4 Day 4
Kularatne 2009 36 7 (2.8) 45 7.3 (3.6) 100% -0.29[-1.68,1.1]
Subtotal *** 36 45 100% -0.29[-1.68,1.1]
Heterogeneity: Not applicable
Test for overall effect: Z=0.41(P=0.68)
Test for subgroup differences: Chi2=2.53, df=1 (P=0.47), I2=0%

Favour corticosteroids -10 -5 0 5 10 Favours placebo

Analysis 2.5. Comparison 2 Steroids versus placebo/no steroids in patients with


dengue at an early stage, Outcome 5 Adverse events in dengue at an early stage.
Study or subgroup steroids placebo Risk Ratio Weight Risk Ratio
n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI
2.5.1 Patients with serious adverse events
Tam 2012 14/75 5/38 49.78% 1.42[0.55,3.64]
Tam 2012 6/75 5/37 50.22% 0.59[0.19,1.81]
Villar 2009 0/87 0/91 Not estimable
Subtotal (95% CI) 237 166 100% 1[0.5,2.03]
Total events: 20 (steroids), 10 (placebo)
Heterogeneity: Tau2=0; Chi2=1.37, df=1(P=0.24); I2=27.04%
Test for overall effect: Z=0.01(P=0.99)

2.5.2 Patients with any adverse events


Tam 2012 23/75 11/38 49.78% 1.06[0.58,1.94]
Tam 2012 16/75 11/37 50.22% 0.72[0.37,1.39]
Villar 2009 0/87 0/91 Not estimable
Subtotal (95% CI) 237 166 100% 0.89[0.57,1.38]
Total events: 39 (steroids), 22 (placebo)
Heterogeneity: Tau2=0; Chi2=0.73, df=1(P=0.39); I2=0%
Test for overall effect: Z=0.53(P=0.6)
Test for subgroup differences: Chi2=0.08, df=1 (P=0.77), I2=0%

Favours steroids 0.01 0.1 1 10 100 Favours placebo

Analysis 2.6. Comparison 2 Steroids versus placebo/no steroids in patients with


dengue at an early stage, Outcome 6 Patients with drug-related adverse events.
Study or subgroup corticosteroids placebo Risk Ratio Weight Risk Ratio
n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI
2.6.1 Hyperglycaemia
Tam 2012 5/75 2/38 66.47% 1.27[0.26,6.23]
Tam 2012 9/75 1/37 33.53% 4.44[0.58,33.74]
Subtotal (95% CI) 150 75 100% 2.33[0.69,7.9]
Total events: 14 (corticosteroids), 3 (placebo)
Heterogeneity: Tau2=0; Chi2=0.95, df=1(P=0.33); I2=0%
Test for overall effect: Z=1.36(P=0.17)

Favour placebo 0.001 0.1 1 10 1000 Favours corticosteroids

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Study or subgroup corticosteroids placebo Risk Ratio Weight Risk Ratio


n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

2.6.2 Hypertension
Tam 2012 0/75 0/37 Not estimable
Tam 2012 0/75 1/38 100% 0.17[0.01,4.1]
Subtotal (95% CI) 150 75 100% 0.17[0.01,4.1]
Total events: 0 (corticosteroids), 1 (placebo)
Heterogeneity: Not applicable
Test for overall effect: Z=1.09(P=0.28)

2.6.3 Pneumonia
Tam 2012 1/75 1/38 100% 0.51[0.03,7.88]
Tam 2012 0/75 0/37 Not estimable
Subtotal (95% CI) 150 75 100% 0.51[0.03,7.88]
Total events: 1 (corticosteroids), 1 (placebo)
Heterogeneity: Not applicable
Test for overall effect: Z=0.49(P=0.63)

2.6.4 Upper respiratory infection


Tam 2012 2/75 0/37 33.43% 2.5[0.12,50.78]
Tam 2012 2/75 1/38 66.57% 1.01[0.09,10.82]
Subtotal (95% CI) 150 75 100% 1.51[0.24,9.41]
Total events: 4 (corticosteroids), 1 (placebo)
Heterogeneity: Tau2=0; Chi2=0.22, df=1(P=0.64); I2=0%
Test for overall effect: Z=0.44(P=0.66)
Test for subgroup differences: Chi2=2.88, df=1 (P=0.41), I2=0%

Favour placebo 0.001 0.1 1 10 1000 Favours corticosteroids

Analysis 2.7. Comparison 2 Steroids versus placebo/no steroids in patients


with dengue at an early stage, Outcome 7 Patients with other reported events.
Study or subgroup corticosteroids placebo Risk Ratio Weight Risk Ratio
n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI
2.7.1 Urticaria
Tam 2012 0/75 0/37 Not estimable
Tam 2012 0/75 1/38 100% 0.17[0.01,4.1]
Subtotal (95% CI) 150 75 100% 0.17[0.01,4.1]
Total events: 0 (corticosteroids), 1 (placebo)
Heterogeneity: Not applicable
Test for overall effect: Z=1.09(P=0.28)

2.7.2 Febrile convulsion


Tam 2012 0/75 0/38 Not estimable
Tam 2012 1/75 0/37 100% 1.5[0.06,35.96]
Subtotal (95% CI) 150 75 100% 1.5[0.06,35.96]
Total events: 1 (corticosteroids), 0 (placebo)
Heterogeneity: Not applicable
Test for overall effect: Z=0.25(P=0.8)

2.7.3 Diarrhoea

Favours placebo 0.001 0.1 1 10 1000 Favours corticosteroids

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Study or subgroup corticosteroids placebo Risk Ratio Weight Risk Ratio


n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI
Tam 2012 0/75 0/37 Not estimable
Tam 2012 0/75 0/38 Not estimable
Subtotal (95% CI) 150 75 Not estimable
Total events: 0 (corticosteroids), 0 (placebo)
Heterogeneity: Not applicable
Test for overall effect: Not applicable
Test for subgroup differences: Chi2=0.9, df=1 (P=0.34), I2=0%

Favours placebo 0.001 0.1 1 10 1000 Favours corticosteroids

Analysis 2.8. Comparison 2 Steroids versus placebo/no steroids in patients with dengue at
an early stage, Outcome 8 Patients with adverse events low-dose steroids versus placebo.
Study or subgroup low-dose cor- placebo Risk Ratio Weight Risk Ratio
ticosteroids
n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI
2.8.1 Patients with serious adverse events
Tam 2012 6/75 10/75 100% 0.6[0.23,1.57]
Subtotal (95% CI) 75 75 100% 0.6[0.23,1.57]
Total events: 6 (low-dose corticosteroids), 10 (placebo)
Heterogeneity: Not applicable
Test for overall effect: Z=1.04(P=0.3)

2.8.2 Patients with any adverse events


Tam 2012 16/75 22/75 100% 0.73[0.42,1.27]
Subtotal (95% CI) 75 75 100% 0.73[0.42,1.27]
Total events: 16 (low-dose corticosteroids), 22 (placebo)
Heterogeneity: Not applicable
Test for overall effect: Z=1.12(P=0.26)
Test for subgroup differences: Chi2=0.12, df=1 (P=0.73), I2=0%

favours placebo 0.005 0.1 1 10 200 favours low-dose steroids

Analysis 2.9. Comparison 2 Steroids versus placebo/no steroids in patients with dengue at
an early stage, Outcome 9 Patients with adverse events high-dose steroids versus placebo.
Study or subgroup high-dose placebo Risk Ratio Weight Risk Ratio
corticosteroids
n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI
2.9.1 Patients with serious adverse events
Tam 2012 14/75 10/75 100% 1.4[0.66,2.95]
Subtotal (95% CI) 75 75 100% 1.4[0.66,2.95]
Total events: 14 (high-dose corticosteroids), 10 (placebo)
Heterogeneity: Not applicable
Test for overall effect: Z=0.88(P=0.38)

2.9.2 Patients with any adverse events


Tam 2012 23/75 22/75 100% 1.05[0.64,1.7]
Subtotal (95% CI) 75 75 100% 1.05[0.64,1.7]

favours placebo 0.002 0.1 1 10 500 favours high-dose steroid

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Study or subgroup high-dose placebo Risk Ratio Weight Risk Ratio


corticosteroids
n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI
Total events: 23 (high-dose corticosteroids), 22 (placebo)
Heterogeneity: Not applicable
Test for overall effect: Z=0.18(P=0.86)
Test for subgroup differences: Chi2=0.41, df=1 (P=0.52), I2=0%

favours placebo 0.002 0.1 1 10 500 favours high-dose steroid

Analysis 2.10. Comparison 2 Steroids versus placebo/no steroids in patients with dengue at
an early stage, Outcome 10 Patients with adverse events low-dose versus high-dose steroids.
Study or subgroup low-dose high-dose Risk Ratio Weight Risk Ratio
steroids steroids
n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI
2.10.1 Patients with any serious adverse events
Tam 2012 6/75 14/75 100% 0.43[0.17,1.06]
Subtotal (95% CI) 75 75 100% 0.43[0.17,1.06]
Total events: 6 (low-dose steroids), 14 (high-dose steroids)
Heterogeneity: Not applicable
Test for overall effect: Z=1.84(P=0.07)

2.10.2 Patients with any adverse events


Tam 2012 16/75 23/75 100% 0.7[0.4,1.21]
Subtotal (95% CI) 75 75 100% 0.7[0.4,1.21]
Total events: 16 (low-dose steroids), 23 (high-dose steroids)
Heterogeneity: Not applicable
Test for overall effect: Z=1.29(P=0.2)
Test for subgroup differences: Chi2=0.81, df=1 (P=0.37), I2=0%

favours high-dose steroid 0.001 0.1 1 10 1000 favours low-dose steroid

ADDITIONAL TABLES

Table 1. Adverse events reported in the included studies


Study ID Number Methods to monitor adverse events Blinding Comment on AE
of partici-
pants Partici- Clinicians
pants

Min 1975 48 No comment unclear unclear No comment

Pong- 7 No comment unclear unclear No comment


panich
1973

Sumarmo 47 No comment blinded unclear No comment


1982

Tassniy- 32 Physical examination, blood test blinded blinded No significant difference be-
om 1993 tween treatment and control
No specific recording of adverse events groups in occurrence of fever af-
Corticosteroids for dengue infection (Review) 37
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Table 1. Adverse events reported in the included studies (Continued)


ter shock, pneumonia, convul-
sion, cardiac arrest, pulmonary
haemorrhage, and positive he-
mo-culture

No specific comments on ad-


verse events

Kularatne 100 Clinical signs recorded at baseline: blinded unclear No comment


2009
mean axillary temperature, headache, nau-
sea, flush, pulse rate, blood pressure

Laboratory tests:

hematocrit and white blood cell count (day


0 to 4)

No specific recording of adverse events

Shashid- 61 No comment not blind- not blind- No comment


hara 2013 ed ed

Tam 2012 150 Prospective adverse events reporting blinded blinded Transient hyperglycaemia in a
small number of cases, but no
active surveillance of patient-reported significant clinical or virological
symptoms and laboratory results adverse events detected
Laboratory tests: full blood count and ran-
dom glucose level daily, with a fasting glu-
cose test performed if the random glucose
test showed a high level

Biochemistry and coagulation profiles, he-


paran sulfate (HS) at day 0 (enrolment)
day, days 5 to 6, and at follow-up 2 to 3
weeks after discharge

Recording: by trained study physicians us-


ing standardized structured case report
form (severity, relatedness of study drugs).
daily recording throughout the disease
course

Reporting: regularly to the Data and Safety


Monitoring Board (DSMB).

Villar 2009 87 Recording: systematic evaluation of ad- blinded blinded No adverse events reported.
verse events during and after drug admin-
istration and monitoring Adverse events reported to the
committee were defined as fa-
Reporting: to an independent committee tal serious adverse effects, life-
to evaluate the safety and efficacy by in- threatening or clinically signifi-
terim analysis. These reports are available cant
immediately, and the final report after 30
days (from protocol).

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Table 2. Duration of dengue-related shock as reported in the relevant included studies


Study ID Measure Duration of shock P value Comments
(statisti-
Corticos- Control cal signif-
teroid group icance)
group

Min 1975 Average 4.8 13.5 P < 0.01 Hydrocortisone hemisuccinate: single dose of 25 mg/kg intra-
hours venous on day 1, 15 mg/kg on day 2, 10 mg/kg on day 3
N = 48 N = 50 (signifi-
Sample cant) 2. No medication
size
Quote: "There was a significant excess in the duration of shock in
the non-steroid group"

Pong- Average 13.5 10.3 P > 0.5 1. Hydrocortisone hemisuccinate: intravenous 25 mg/kg/day; 5
panich hours mg/kg at start, rest given in divided doses every four to six hours
1973 (3 to30) (1 to23) (not sig-
(range) nificant) 2. No medication
N=7 N =19
Sample Quote: "Duration of shock showed no statistically significant dif-
size ference between the two programs of treatment"

Study ID Time pe- Participants per time P value Comments


riod period of shock (N)

Corticos- Control
teroid group
group (N
= 47) (N = 50)

Sumarmo 0.5 to 2.4h 31 28 Not re- 1. Hydrocortisone hemisuccinate: 50 mg/kg, single intravenous
1982 ported dose
2.5 to 4.4h 12 13
2. Placebo: sodium chloride 0.9%
4.5 to 6.4h 4 3
Quote: "there was no significant differences between the treat-
6.5+h 3 3 ment groups"

Table 3. Sample size calculations for corticosteroids in dengue-related shock and in dengue at an early stage versus
placebo or no intervention
Outcome Assumed risk Source Clinically Sample size Sample
important required1,2 size in
relative re- meta-
duction analysis

Dengue-related shock

Death 21.3% Analysis 1.1 25% 1.672 284

Need for blood transfusion 24.0% Analysis 1.2 25% 1.440 89

Pulmonary haemorrhage 3.2% Analysis 1.3 25% 13.348 63

Convulsions 1% (assumed, in- Analysis 1.3 25% 43.576 63


stead of 0%)

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Table 3. Sample size calculations for corticosteroids in dengue-related shock and in dengue at an early stage versus
placebo or no intervention (Continued)
Dengue at an early stage

Dengue-related shock 4.7% Analysis 2.1 25% 8.568 286

Severe bleeding 0.6% Analysis 2.1 25% 72.886 425

Severe thrombocytopaenia 2.6% Analysis 2.1 25% 16.518 225

ICU admission 7.5% Analysis 2.1 25% 5.318 286

Ascitis 4.4% Analysis 2.1 25% 9.600 178

Death 1% (assumed, in- Analysis 2.1 25% 43.576 664


stead of 0%)

1 The sample size was calculated for binary outcomes for superiority trials. We estimated that a 25% reduction of risk to develop a
complication in the intervention group when compared to the control group would be clinically important. The "assumed risk" is the risk
in the control group. All calculations are based on: 2-sided tests, with a ratio of 1:1, power of 0.8, and confidence level of 0.95.
2 All calculations were performed using the software available at http://www.sealedenvelope.com/power/binary-superiority/.

APPENDICES

Appendix 1. Search strategy

Search CIDG SRa CENTRAL MEDLINEb EMBASEb LILACSb


set

1 adrenal cortex adrenal cortex exp DENGUE exp DENGUE dengue


hormone hormone

2 corticosteroids corticosteroids dengue dengue corticos-


teroids

3 hydrocortisone hydrocortisone HEMORRAGIC FEVER HEMORRAGIC FEVER dexam-


ethasone

4 dexamethasone dexamethasone hemorrhagic fever hemorrhagic fever pred-


nisolone

5 methylpred- methylpred- ('break-bone fever').ti,ab ('break-bone fever').ti,ab 2 or 3 or 4


nisolone nisolone

6 prednisolone prednisolone 1 or 2 or 3 or 4 or 5 1 or 2 or 3 or 4 or 5 1 and 5

7 hemorrhagic fever hemorrhagic fever ADRENAL CORTEX HOR- adrenal cortex hormones —
MONES

8 dengue fever dengue fever corticosteroids corticosteroids —

9 1 or 2 or 3 or 4 or 5 1 or 2 or 3 or 4 or 5 steroid* steroid$ —
or 6 or 6

Corticosteroids for dengue infection (Review) 40


Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cochrane Trusted evidence.
Informed decisions.
Library Better health. Cochrane Database of Systematic Reviews

(Continued)

10 7 or 8 7 or 8 cortisol* cortisol$ —

11 9 and 10 9 and 10 HYDROCORTISONE HYDROCORTISONE —

12 — — hydrocortisone hydrocortisone —

13 — — DEXAMETHASONE DEXAMETHASONE —

14 — — dexamethasone dexamethasone —

15 — — METHYLPREDNISOLONE METHYLPREDNISOLONE —

16 — — methylprednisolone methylprednisolone —

17 — — PREDNISOLONE PREDNISOLONE —

18 — — prednisolone prednisolone —

19 — — 7 - 18/OR 7- 18/OR —

20 — — 6 and 19 6 and 19 —

21 — — Limit 20 to human Limit 20 to human —

aCochrane Infectious Diseases Group Specialized Register.


bSearch terms used in combination with the search strategy for retrieving trials developed by The Cochrane Collaboration (Higgins 2011;
upper case: MeSH or EMTREE heading; lower case: free text term.)

WHAT'S NEW

Date Event Description

15 November 2016 Amended corrected link in methods section

HISTORY
Protocol first published: Issue 1, 2002
Review first published: Issue 3, 2006

Date Event Description

10 June 2014 New search has been performed Objectives: we included studies evaluating steroids given early
in dengue to prevent the disease, and adjusted the inclusion cri-
teria and search strategy.We improved the assessment of risk of
bias and calculated the optimal sample size to help interpret our
results.

10 June 2014 New citation required but conclusions Authors: changed from Panpanich R, Sornchai P and Kanja-
have not changed naratanakorn K to Zhang F and Kramer CV.

Corticosteroids for dengue infection (Review) 41


Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cochrane Trusted evidence.
Informed decisions.
Library Better health. Cochrane Database of Systematic Reviews

CONTRIBUTIONS OF AUTHORS
Both review authors contributed to the development of the review, extraction of the data, data analysis, and presentation and
interpretation of the results.

DECLARATIONS OF INTEREST
None known.

SOURCES OF SUPPORT

Internal sources
• Liverpool School of Tropical Medicine, UK.

External sources
• Department of International Development, UK.

DIFFERENCES BETWEEN PROTOCOL AND REVIEW


In this review update, we focus not only on the dengue shock, but also the early dengue. The changing of the scope is the only difference.

INDEX TERMS

Medical Subject Headings (MeSH)


Adrenal Cortex Hormones [*therapeutic use]; Blood Transfusion [statistics & numerical data]; Randomized Controlled Trials as Topic;
Severe Dengue [*drug therapy] [mortality]; Shock, Hemorrhagic [*drug therapy] [mortality]

MeSH check words


Adult; Child; Humans

Corticosteroids for dengue infection (Review) 42


Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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