Best Practice in Dengue infections

Professor Siripen Kalayanarooj

Consultant, WHO Collaborating Centre for
Case Management of Dengue/ DHF/ DSS
(Director 1997-2015),
Queen Sirikit National Institute of Child Health,
Bangkok, Thailand
 Reported dengue cases in
Thailand: 1958 - 2016

174,286
200000
115,768
144,952
150000 101,689
100000
53,189
50000
38,768 68,386
2,158
0
1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53 55 57 59

สำนักระบำดวิทยำ กรมควบคุมโรค กระทรวงสำธำรณสุข

 CFR of dengue in Thailand: 1958 - 2016

13.9
14
12
10
8
6
4 3.16
1.95
2
0.58 0.34 0.10
0
2 5 8 11 14 17 20 23 26 29 32 35 38 41 44 47 50 53 56 59

สำนักระบำดวิทยำ กรมควบคุมโรค กระทรวงสำธำรณสุข

 Reported cases of dengue
2014-2017

2012 2013 2014 2015 2016

Morbidity 150,174 40,278 142,925 63,310 53,189
Dead 131 41 148 61 63
CFR 0.09 0.10 0.1 0.09 0.10
 Age incidence of
Dengue
• 1958-1987: Only children were
affected (Age < 15 years)
• 1987-1997: Adult reports 10-15%
• 2009:Children = Adults
• 2010 – 2014: Adults 54%
• 2015: Adults 64.4% Dead 66.2%
• 2016: Adults 62.1% Dead 49.2%
 เปรียบเทียบจำนวนผู ป ้ ่ วยไข้เลือดออก
เด็กและผู ใ้ หญ่
พ.ศ. 2539 -2559
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 58 59
Children Adult

สำนักระบำดวิทยำ กรมควบคุมโรค กระทรวงสำธำรณสุข

Peak incidence of dengue
infections: 2017

Age range (year) %

15-24 26.65

10-14 20.11

25-34 14.59
 Situation in Thailand
2016-2017
• 60% in adults
• 40% in children
• CFR 0.10%
o Children 30%
o Adults 70%
• Oldest age 92 years!
• Youngest – before birth!!! (Vertical
transmission)
 Dengue Serotypes
Queen Sirikit National Institute of
Child Health 1973-2015 (April 15)

AFRIMS
 Dengvaxia
SanofiPasteur
• Age >9 – 45 Years, dosage 0,6, 12 months
• Efficacy – 65%
o Against Den 1 – 50%
o Against Den 2 – 40%
o Against Den 3 – 70%
o Against Den 4 – 70%
• Reduce hospitalization 80%
• Reduce severity 90%
Not use in sero-negative individual
Repeated infections – more severe
ADE – Antibody Dependent Enhancement
 Dengue virus infection
10,000

Asymptomatic Symptomatic
9,000 1,000

Viral syndrome Dengue fever DHF

500 400 100
Plasma leakage
Expanded dengue syndrome
1. Prolonged shock: liver failure, DHF
renal failure,…Encephalopathy… DSS
2. Co-morbidities
3. Co-infections
4. True dengue infection - encephalitis
1-5
 Management targets on
DHF/DSS with plasma leakage

• Among 1,000 dengue patients,

probably 100 DHF with plasma
leakage and 10-50 DSS (depends on
early detection of plasma leakage)
• Majority of dengue patients are not
severe

No predictors of severe diseases at present

 Dengue Fever
(Infection)
• Headache
• Retro-orbital pain
• Myalgia
• Arthralgia/ bone pain (break-bone fever)
• Rash
• Hemorrhagic Manifestations
• Leukopenia (WBC < 5,000 cells/ mm3)
• Platelet count ≤ 150,000 cells/mm3
• Rising HCT 5-10%

Diagnosis :

Tourniquet test positive + WBC  5,000 cells/cu.mm

(positive predictive value = 83%)
 Dengue Hemorrhagic Fever
Clinical
• High, continuous fever 2-7 days
• Hemorrhagic manifestations: tourniquet test positive,
petechiae, epistaxis, hematemesis, etc…
• (Liver enlargement)
• (Shock)
Laboratory
• Evidence of plasma leakage; rising Hct ≥ 20%, pleural
effusion, ascites, hypoalbuminemia (serum albumin < 3.5
gm% or <4 gm% in obese patients), UTZ
• Platelet count ≤ 100,000 cells/ mm3.

Note: Patients who have definite evidence of plasma

leakage, hemorrhagic manifestations and
thrombocytopenia might not be present as the exception.
 Severity of DHF

 Grade I – No shock
 Grade II – No shock, spontaneous
bleeding
 Grade III – Shock
 Grade IV – Profound shock
(immeasurable BP/ Pulse)
 Pathophysiologic
Hallmark of DHF

• Plasma leakage – major problems

• Abnormal hemostasis - usually minor
bleeding in early febrile phase except
in those with underlying peptic ulcer
or those who took NSAID, Aspirin,
Steroid
 Natural course of DHF
Day 1 2 3 4 5 6 7 8 9

Fever Shock

Pleural effusion,
Ascites
Hematocrit

Plasma leakage Stop leakage Reabsorption

IV fluid: NSS, DAR, DLR

W Colloid: 10%Dextran-40
B M+5% Deficit
C (= 4,600 ml in adult)

WBC 6,000-9,000 ≤5,000

Platelet count 200,000 ≤100,000 <50,000
Hct 35 38 45 (rising 20%)
Albumin ≤3.5 gm%
Cholesterol ≤100 mg%
Professor Siripen Kalayanarooj
 Important steps in
Dengue Case management

1. Early diagnosis of dengue infections

2. Early detection of plasma leakage
and proper IV fluid management
3. Detect and correct common
complications: ABCS, Fluid overload
4. Management of bleeding
5. Dx & Management of unusual cases:
BBH
 Prolonged shock
• > 10 hours untreated - Death!!!
• > 4 hours untreated
Liver failure- prognosis 50%
Liver + Renal failure - prognosis10%
3 organs failure (+respiratory failure)
– Prognosis is a miracle!!!
 Compare using different
classifications at QSNICH
WHO 1997, 2011 WHO 2009
• OPD (2009):
o 1,500 cases (TT positive • Increase to 30,000 cases
+ Leukopenia) when applying only 2
warning signs (abdominal
pain and vomiting)

o IPD (3 months in 2009)

o 100 DHF/DSS cases for • Increase to 300 SD for
close monitoring close monitoring
 Lahore, Pakistan Experienced
(Sep.-Nov. 11)

• Total suspected cases : 600,000 cases

• Confirmed 20,000 cases (< 4%)
• At the peak: 4,000-6,000
patients/day
• Admission 500-600 cases/day
• Death 10-15 cases per day
 Multi-country study: 18 countries
Validation study of the revised classification

Revised not Dengue Dengue Severe Total

classified without With dengue
Warning Warning
Signs Signs

Not classify 23 57 159 29 268

DF 7 551 684 75 1,317

DHF 2 8 240 39 289

DSS 0 0 12 76 88

Total 32 616 1,095 219 1,962

Barniol J et al: BMC Infectious Disease 2011,11: 106

 Warning signs

• Non-specific, low specificity (20- 50%)

• Increase workload beyond management by
existing healthcare personnel
o 20 times at OPD
o 3 times at IPD
 High risk patients

• Infants, Elderly, Pregnancy

• Obese patients
• Prolonged shock
• Significant Bleeding
• Encephalopathy
• Underlying diseases
 Causes of Deaths in Dengue

• Missed/ Delayed diagnosis > 50-80% ;

Including EDS
• Fluid overload: Acute pulmonary
edema, CHF >70%
• Prolonged shock: Late coming to the
hospital, not detect & correct complications
• Massive bleeding: prolonged shock, Drugs
induced gastritis (Aspirin, NSAID,
Steroid), Peptic ulcer
 Important steps in
Dengue Case management
1. Early diagnosis of dengue infections
2. Early detection of plasma leakage and
proper IV fluid management
3. Detect and correct common complications:
ABCS (Acidosis, Bleeding, Hypocalcemia,
Hypoglycemis), Fluid overload
4. Management of bleeding
5. Dx & Management of unusual cases: BBH
 1. Early clinical Diagnosis

• Think of dengue in every patients who

present with high fever (except in adults)
• High continuous fever
• Bleeding manifestations: petechiae,
epistaxis, gum bleeding, hematemesi,
melena, hematuria, hemoglobinuria,
menstruation, abnormal vaginal bleeding…
• Ache and pain; headache, retro-orbital
pain, myalgia, arthralgia/ bone pain
• Rash; Petechial, MP-rash
 Case 1 : 21-year-old,
129 Kgs
• Fever for 5 days
• Headache
• Bodyache
• Poor appetite
• Nausea, no vomiting
• Loose stool 2
times/day since
yesterday
• T 39 degree, BP
100/70 mmHg, P
94/min, RR 20/min
• Others – WNL, no
skin rash
 CBC
• Hb 15.1 gm%, Hct 45%, wbc
4,350, P 67, L 25, AL 8, platelet
35,000 cells/cumm.
 LFT
• Albumin 3.6 gm% (normal > 4.0
gm%), AST 286, ALT 156 U

Supine upright
 Follow up the next day (Day 6)

• Fever 38.1, BP 100/60, P

90, RR 20
•Still nausea, no vomiting
•Poor appetite
•Hct q 6 hrs revealed:
dropped from 45% to 43%,
42% and 41% this morning
Urine
Urine blood +2, prot 3+,
no RBC, no wbc
 Lessons Learnt

1. Early diagnosis of dengue infections

• CBC: WBC, Platelet count, Hct - Not done
even though they can refer patients to be
done in the nearest hospital (recommend to
do CBC starts from day 3 of illness – clinical
or warning signs cannot help to detect
plasma leakage)

• No NS1Ag available but most people prefer

this even though it does not guide clinicians
for IV fluid management
 Dengue diagnostic options and sensitivity
Fever phase (D1-5)
NS1Ag – sensitivity 40-70%
- specificity 99%
100
PCR
80 IgM
% sensitivity

NS1
60
viral culture
40

20
Late phase (D>5)
0 Dengue IgM – sensitivity 60% on shock day
0 1 2 3 4 5 6 7 8 - specificity 99%
Day of illness

Courtesy of Armed Forces Research Institute of Medical Sciences

 2. Early detection of plasma leakage
and proper IV fluid management

Evidence of Plasma Leakage

• Rising Hct ≥ 20%
• Pleural effusion, ascites
o Physical examination
o CXR – Right lateral decubitus
o Ultrasound
• Hypoalbuminemia
o Albumin < 3.5 gm% in normal patients
o Albumin < 4 gm% in obese patients
 Lessons Learnt
Delay detection of plasma leakage - major
cause of fluid overload and possible lead to
dead
o Not isotonic
o Too early
o Too much
o Too long
o No Dextran available (other colloidal solutions
are not effective including albumin)

Too little - causes prolonged shock and organs failure

 Indication for IV fluid in
DHF patients

• Entering critical period – thrombocytopenia;

platelet count ≤ 100,000 and throughout plasma
leakage time, 1-2 days (and 12-24 hours beyond)
• Shock: difficult to detect because patients are in
good consciousness, able to walk and talk
• Not before and after stop leakage, if IV fluid is
extend beyond this leakage phase, patients are at
risk of fluid overload which is one of the major
causes of death
 Principles of IV fluid in DHF
patients during leakage period

• Isotonic salt solution: NSS, DAR, DLR with

or without dextrose
o Check blood sugar if given IV without dextrose
o 30% of DSS patients have hypoglycemia
• Limited amount of fluid (oral + IV) during
leakage period (M +5% deficit or 4.6 L in
adults) – If give more IV fluid, more
leakage that will interfere with respiration
o If more volume is needed, switch to Dextran-40
(hyper-oncotic), plasma expander
 Principles of IV fluid in DHF
patients during leakage period

• Adjust rate of IV fluid according to monitoring

parameters: clinical, vital signs, Hct and amount of
urine
• Discontinue IV fluid when reabsorption occurs
(convalescence phase; stable Hct, diuresis,
bradycardia, convalescence rash)
 Dengue Shock Syndrome

Plasma leakage Bleeding

• Narrowing of Pulse
Pressure ≤ 20 mmHg
• Hypotension
• Systolic < 80 in adult
• < 70 + (Age in year X
2) in children
• Orthostatic hypotension
• Fainting

Adults have more significant bleeding

Aware of significant bleeding in:
- Patients with menstruation or abnormal vaginal bleeding
- Hemoglobinuria
- Severe abdominal pain (concealed GI bleeding)
 Other causes of shock
in Dengue patients
• Hypoglycemia
• Excessive vomiting
• Co-infections
 Rate of IV fluid

Shock Non-shock

RateofIV Fluidin RateofIV Fluid in

DengueShockSyndrome DengueHemorrhagicFevergradeI& II

10-5ml/kg/hr(300-500ml/hr) 7ml/kg/hr(100-120ml/hr)

8
5ml/kg/hr(100-120ml/hr)
10
6
8 3ml/kg/hr(80-100ml/hr) 1.5ml/kg/hr(40ml/hr) 3-5ml/kg/hr(80-120ml/hr)
6 3-1ml/kg/hr(40-80ml/hr) 4
4
2
2
Rate Rate
0 0
0 6 12 18 24 Hoursaftershock 0 6 12 18 24 30 36 42 48 Hour safter
leakage

(Rate in adult)
DSS – NSS (D) 10 ml/kg/hr or 500 ml/hr in adult,
If profound shock – free flow 15-30 mins, then reduce rate
Non-shock: rate depends on degree of
thrombocytopenia & rising Hct
 3. Detect and correct
common complications:
• A – Acidosis – Prolonged shock with possible
liver/ renal failure
• B – Bleeding – No rising Hct or dropping
Hct
• C – Hypocalcemia and other electrolyte
imbalance (Hypokalemia, hyponatremia)
• S – Hypoglycemia (30% in DSS)
• Fluid overload – Signs & symptoms of fluid
overload
 Practical management when no lab.
for correction of A, B, C & S

• Check Blood Sugar

• 10% Ca gluconate 10 ml dilute to 20 ml
IV push in 10 min (1 ml/kg/dose,
maximum dose 10 ml)
• Vitamin K1 IV 10 mg
• NaHCO3 1 ml/kg IV if cyanosis or
persisted cold, clammy skin after IV
fluid resuscitation
 Indications for switching
to colloidal solution
• Signs and symptoms of fluid overload
o Puffy eyelids, distended abdomen with ascites
o Dyspnea/ Tachypnea
o Positive lungs signs: crepitation, rhonchi,
wheezing
• Continue rising Hct
• Persistent high Hct > 25-30%
• Too much crystalloid solutions before
plasma leakage
 Type of Colloidal solution
used in DHF/DSS

• Plasma expander (high osmolarity,

high oncotic pressure than plasma)
o 10% Dextran-40 in NSS
• Plasma substitute
o 6%Dextran-70 or 6%Dextran-40
o Starch
o Gelatin
 Dextran infusion
(10% Dextran-40 in NSS)

• Dextran rate 10 ml/kg/hr or 500 ml in adults

• Dextran will bring down PCV by 10 points, but
not below baseline PCV
If Hct drops > 10 points or below baseline –
Think of bleeding
• Maximum dose per day = 30 ml/kg/day (may
be used up to 60 ml/kg/hr in 48 hrs)
• All through the course, may use up to 6 doses
• Aware of sticky urine
 Management of fluid overload

• Insert urinary catheter

• Furosemide 1 mg/kg/dose IV (with or
without dextran)
• Record vital signs q 15 min X 4 times
• After 1 hr, change IV to crystalline
solution at the rate appropriate for
the timing
o 1 ml/kg/hr if overt signs of fluid overload
and adjust the rate of IV according to
urine output (0.5 ml/kg/hr)
o KVO if pass the critical period
 Dextran + furosemide
(in the middle or after 10-15 mins)

• Shock
Plasma leakage :
Natural course in severe cases
Shock

• During critical period, Equilibrium

Reabsorption

• Not in reabsorption phase

Start Stop

0 24 48 72 hours
Plt < 100,000 cells/cumm

Hct

Furosemide depletes intravascular volume,

(not deplete ascites or pleural effusion)

Dextran holds intravascular volume or

draws back ascites and pleural effusion
 4. INDICATION
FOR BLOOD TRANSFUSION

• Significant blood loss: > 10% of total blood

volume (> 6-8 ml/kg)
• HCT dropping but no clinical improvement in
spite of adequate volume replacement
(Usually blood transfusion when HCT 40-45%)
• No rising HCT enough to explain shock
(Usually rising HCT about 20-30% from
baseline for shock)
 AMOUNT OF BLOOD REPLACEMENT

• Transfuse equal to the amount of estimated loss

(if can estimate the amount of blood loss)
• Transfuse 10 ml/kg or 1 unit of whole blood if cannot
estimate the blood loss or 5 ml/kg of packed red cell
(PRC) if the patients have signs of fluid overload
• Do the HCT before and after transfusion to access the
rising HCT (about 5 points in children for the above
recommended dose)
* Rate of transfusion depend on the patients’ conditions
– usually as rapid as possible in 1-2 hours
 ROLE OF PLASMA IN DHF/DSS

• Almost no role !!!

o The osmolarity of plasma is equal to the
patients’plasma so it will not hold the plasma
volume and it will leak into the pleural and
peritoneal spaces
o To correct the abnormal coagulogram, the
dose is 40-50 ml/kg (equal to the patients’
plasma volume). There is no available space
for that large volume
 INDICATION FOR PLATELET TRANSFUSION

• Significant blood loss. Indicate for all cases that need

blood transfusion.
• Platelet transfusion is only the adjunct therapy. If no
platelet concentrate available, the patients will recover
anyway.
• Even with indication for platelet transfusion, if those
patients have signs of fluid overload, platelet
transfusion is contra-indicated! For it may cause life-
threatening heart failure or acute pulmonary edema.
 PLATELET PROPHYLAXIS

• No prophylaxis platelet transfusion in children even for

those patients who have very low platelet count (< 10,000
cell/mm3)
• In adult patients who had underlying hypertension or
heart diseases and platelet count < 10,000 cells/mm3,
prophylaxis platelet transfusion is recommended.
 Plasma leakage :
Natural course in severe cases
Shock
Early Late convalescence

Equilibrium
Reabsorption

Start Stop

0 24 48 72 hours
Plt < 100,000 cells/cumm

Hct
 Convalescence

• A – appetite
• B – bradycardia
• C – Convalescence rash, itching
• D – Diuresis: aware of Hypokalemia
 5. Management of Unusual/
Complicated cases

• Cases present with shock and high

fever ±
• Platelet < 100,000 cell/cumm. especially
< 50,000 cells/cumm.
• Bleeding
• Look for evidence of plasma leakage:
rising Hct, albumin < 3.5 gm% or < 4
gm% in obese patients, ascites, pleural
effusion by CXR, UTZ
 If evidence of plasma leakage

Look for complications:

oDSS with superimposed bacterial

infections
oDSS with concealed bleeding
oDSS with hepatitis (liver injury,
liver failure)
 Shock with fever
DSS VS Septic shock
DSS
• Platelet usually ≤ 50,000
cells/cumm
• ESR ≤ 20 (usually < 5
mm/hr)
• Evidence of plasma leakage
(pleural effusion, ascites)
by UTZ, low serum albumin
• LFT:
o Albumin < 3,5 gm% in
normal person (< 4 in obese
person)
o Elevation of AST/ALT
Septic shock
• Platelet is not ≤ 50,000
cells/cumm at first
presentation
• ESR - > 30 mm/hr
• No evidence of plasma
leakage
• LFT
o Normal albumin > 3,5 gm%
o Mild or no elevation at
presentation
 Lessons Learnt
5. Management of unusual cases
• No experience and often misdiagnosis
with septic shock or other diseases
• Patients came late with prolonged
shock and organs failure
• Patients came with co-morbidity/ co-
infections
 DSS vs Hypovolemic shock
(Diarrhea)
DSS Hypovolemic shock
• Mild to moderate • Severe dehydration
dehydration
• Rising Hct ≥ 20% • Rising Hct not > 10%
• May have history of • History of massive
few loose stool watery diarrhea
 Not typical as DSS
• No leukopenia – Leukocytosis and
increase PMN
• No rising Hct – (Concealed) bleeding
• CXR - Portable and very difficult to
detect pleural effusion
• Clinical: Pleural effusion & ascites -
Too late when detect
Usually misdiagnosed as Septic Shock
Especially in adults
Thank you !!!