A RANDOMIZED CONTROLLED TRIAL OF ZINC

SUPPLEMENTATION AS ADJUVANT THERAPY FOR

DENGUE VIRAL INFECTION IN THAI CHILDREN
Supervised by : dr. Ambarsari L., Sp.A
Presented by : Cerellia Clarissa 201706010089
INTRODUCTION
 PICO

Problem • Children with dengue fever / dengue hemorrhagic fever

Intervention • Zinc supplementation 3 x 15mg per day for 5 days or until defervescence

Comparison • Placebo

• Primary  defervescence phase by assess defervescence time of dengue infection

Outcome • Secondary  estimate the duration of hospitalization, the presence of severe DVI
and prevalence of zinc deficiency

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 INTODUCTION

most rapidly spreading

mosquito-borne viral disease in
the world

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 INTRODUCTION

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 LATAR BELAKANG

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 LATAR BELAKANG

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 INTRODUCTION

◆ > 860.000 cases of dengue (2000-2011)

◆ Average incidence of 115 cases / 100.000
persons
◆ 2003-2011
◆ Average DHF CFR  0.05% (0.03-0.09)
◆ Average DSS CFR  4.45% (4.04-5.92)
◆ Highest morbidity and mortality in children
15 yo
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 INTRODUCTION

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 INTRODUCTION

◆ Component of >300 enzymes involved in

catalysis, redox regulation, signaling and
development of neurons.
◆ Essential for the immune system
◆ Deficiency  dramatic implications for
immune function  the risk for several
infectious diseases (diarrhea,
pneumonia, malaria)
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 INTRODUCTION

◆ Zinc deficiency is common in developing countries

◆ Thailand  estimated risk for zinc deficiency > 40%
◆ Children with DF, during the toxic phase  serum zinc levels  (esp
in children with diarrhea, dual bacterial inf , DSS, hepatic
encephalopathy)
◆ Clinically relevant threshold and relationship between zinc levels and
DVI severity  CONTROVERSIAL
◆ This RCT  assess the effect of zinc supp on the outcome of DVI
children
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METHODS
 STUDY DESIGN

STUDY Randomized, double-blind,

DESIGN placebo-controlled trial

- January 2016 – April 2017

- Pediatric unit of MSMC LOCATION
& TIME
Srinakharinwirot University
Hospital , Thailand

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 POPULATION
INCLUSION CRITERIA (≥2)

• Nausea & vomiting

• Rash
• Aches and pain
• Tourniquet test +
• Leukopenia (5000/mm3)
• Dengue serology test + (IgG/IgM dengue / NS1)
• Warning signs (abdominal pain, persistent vomiting, clinical fluid accumulation,
mucosal bleeding, lethargy, liver enlargement > 2 cm , Ht with  platelet)

EXCLUSION CRITERIA

• < 1 YO
• Regularly assumed vitamins or minerals
• Chronic systemic diseases
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 INTERVENTION

Zinc supplementation group Placebo group

Bis-glycinate zinc (15 mg elemental zinc) Oral rehydration solution with identical
Prepared in powder form in single-dose flavor and packaging
sachets and dissolved in water

Treatment of dengue infection, observation and

discharge decision  done by physicians who
were not involved in the study
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 DATA COLLECTING

◆ Baseline demographic characteristics and anthropometric data

◆ Detailed medical history
◆ Physical examination (1st day of hospitalization and every 24 h)
◆ Vital signs every 4 hours  by nurse
◆ Blood samples taken at the admission (CBC, dengue serology test,
serum albumin, alanine/aspartate transaminase, serum zinc levels)
◆ ELISA  dengue-specific IgG/IgM
◆ Lateral flow chromatographic immunoassay (Dengue Combo Test Kid) 
NS1
◆ Flame atomic absorption spectrometry (before and 72 hours after
supplementation)  serum zinc level
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 Normal serum zinc levels

◆ Male, females
<10 yo
≥10 yo ≥10 tahun
• Morning 65 g/dL • Morning fasting 70 • Morning-fasting 74 g/dL
• Afternoon 57 g/dL g/dL • Morning non-fasting70
• Morning nonfasting 66 g/dL
g/dL • afternoon 61 g/dL
• afternoon 59 g/dL

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 Fever criteria

◆ Fever  body temp ≥37.8oc

◆ Defervescence of fever 1st time that body temp
falling to normal level(<37.8oc) for 2 consecutive
measurements of 4h interval

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 OUTCOME

◆ Primary outcome
◆ Defervescence phase  assess
defervescence time of dengue inf.

◆ Secondary outcome
◆ Duration of hospitalization
◆ Presence of severe DVI
◆ Prevalence of zinc deficiency
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 STATISTICAL ANALYSIS

◆ Variables distribution one-sample Kolmogorov-

Smirnov test
◆ Normally distributed means & SD
◆ Nonnormally distributed  median &
interquartile range
◆ Compare proportions between groups
Pearson’s Chi square atau Fisher’s exact test
◆ Verify the differences of normally distributed
and nonnormally distributed variables 
student t-test & Mann-Whitney U-test
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 RESULTS

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 HASIL

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 DISCUSSION

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 Zinc dan lama rawat inap

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 ◆ This study 1st RCT
◆ Other studies systematic review  in the presence
of zinc deficiency of malnutrition  zinc supp  the
average duration of diarrhea and  the number of
children whose diarrhea persisted until 7 days
◆ Zinc supplementation  clinically beneficial for
children > 6yo
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 Zinc roles in some diseases

Zinc supp was Zinc deficiency  Still controversial

safe &  diarrheal highly prevalent
morbidity,
without adverse Zinc  not affect
effects on disease clinical outcomes
progression

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 Zinc and DVI severity

Zinc levels significantly differed in children with DF, DHF or DSS

No evidence that serum zinc level was a risk factor for the Yuliana et al.
development of severe DVI

Clinical severity of dengue was similar in the low & high zinc groups, Widago
while the number of lymphocytes was significantly different

Toxic phase most of the patients had a moderate (40-60 g/dL) or Laoprasopwattana et al
marked (<40 g/dL) decrease in plasma zinc levels

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 ◆ Zinc essential micronutrient normal development
and function of cells mediating nonspecific immunity
◆ Zinc deficiency prevents outgrowth of T lymphocytes,
activation, Th1 cytokine production & B lymphocytes
help
◆ Studies in experimental human models  CD8+ CD73+ T
lymphocytes, required for antigen recognition,
proliferation and cytolisis were decreased in zinc def
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 Enteroaggregative E.coli induced
diarrhea

Zinc deficienct

Weight loss  ,  stool shedding, 

mucus production & reduced the
infiltration of leukocytes into the ileum

Impaired immune response

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 KETERBATASAN PENELITIAN

◆ Limited population size

◆ Both treatment and discharge depended on attending

physicians

◆ Zinc in food intake was not assessed during the follow up

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 CONCLUSIONS

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 ◆ zinc supplementation at the admission may
contribute to shorten the hospital staying.
◆ Normal serum zinc levels at the baseline and zinc
supplementation during the acute phase of the
disease improve the clinical outcomes regarding
fever duration.

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 CRITICAL
APPRAISAL

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 Are the results of the trial valid ?

Was the assignment of patients to treatments randomised?

• Yes

Was the randomization list was hidden ?

• Yes.

Were the groups similar at the start of the trial ?

• Yes. Number of participants in each group are the same, and the demographic
characteristics & antropometric data are almost equally the same
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 Are the results of the trial valid ?

Aside from the allocated treatment, were groups treated equally?

• Yes, examination and therapy were done qually.

• Control group  ORS with identical flavor and packaging

Were all patients who entered the trial accounted for ? And were
they analysed in the groups to which they were randomised?

• Yes, 50 participants were randomised and 50 participants were analysed

Were measures objective or were the patients and clinicians kept

“blind” to which treatment was being received?

• Yes. This study was a double-blinded study and the physicians that responsible for
the patients did not involved in the study
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 Conclusion :
the results of the trial
valid
 Will the result help me in caring for my patient ?

Is my patient so different to those in the study that the results

cannot apply
• No, out patients are similar

Is the treatment feasible in my setting ?

• Yes

Will the potential benefits of treatment outweigh the potential

harms of treatment for my patient ?
• Yes. Because in this study shows that zinc supplementation can shorten hospitalization
time and shorten the deverfescence time

Will this study’s result will change our management of therapy??

39 • yes
 Conclusion :
this result can be applied

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 THANKYOU!

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