dengue epidemic: what we know so far tan cheng...

DENGUE EPIDEMIC:

WHAT WE KNOW SO FAR

TAN CHENG CHENG

INTENSIVIST

SULTANAH AMINAH JOHOR BAHRU

Dengue Virus Genome

−A single stranded RNA −Genome is about 11000 ribonucleotides, encoding 3 structural proteins

and 7 non-structural proteins

−Structural proteins: capsid protein (C), membrane protein (M) and envelope protein (E)

−The non structural proteins: NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5

−The proteins are involved in the various stages of the dengue viral replication

−The envelope protein (E) is involved in the initial attachment of the virus particles on host cells

2

Dengue Virus

−4 serotypes, namely DenV 1, DenV 2, DenV 3 and DenV 4

−Further Classification into genotypes is dependent on the geographically region where the virus was isolated

−The number of genotypes for each serotype are as follows: DenV 1 (5), DenV 2 (6), DenV 3 (5) and DenV 4 (3)

−Malaysia “hyperendemic” as all serotypes could be isolated at any point of time

3

4

0%

10%

20%

30%

40%

50%

60%

70%

DENV1 DENV2 DENV3 DENV4

DENGUE SEROTYPES

YEAR 2013, 2014 AND 2015

2013 2014 2015

1992-1995: DENV3

1998-2000: DENV2

2001-2002: DENV3

2004-2006: DENV1

2008-2009: DENV3

NO PREDICTABLE CYCLE FOR DEN V

INFECTION

5

• Four-year cycle outbreaks:

1974, 1978, 1982, 1986, 1990

• No predictable cycle from 1991

• Three-year cycle outbreak from 2008

• Yearly cycle outbreak from 2012

• Usually an outbreak whenever there was a

change in the dengue virus serotype as fewer

people would be immune to the serotype after

the change

• Each individual can have 4 times of Den V

infection in his/her lifetime

Serological Profile

6

ADE: ANTIBODY-DEPENDENT ENHANCEMENT OF DENV

INFECTION ADAPTED FROM TAKADA AND KAWAOKA, 2003

Virus bound to Ab, is able to enter macrophages via the Fc receptor

This makes the infection of macrophages more efficient and leads to the infection of a large number of macrophages, leading in turn to a more severe clinical presentation

According to this hypothesis, DHF/DSS should occur only when there is more than one serotype of DV circulating in a specific area

7

http://microbewiki.kenyon.edu/images/0/0e/AD_enhancement_figure.jpg

8 microbewiki.kenyon.edu

https://microbewiki.kenyon.edu/index.php/Effects_of_Pathogen-Vector_Interactions_on_the_Transmission_of_Dengue_Virus

DENGUE INCIDENCE RATE & CASE FATALITY RATE

FOR YEAR 2000-2014, MALAYSIA

9

DENGUE CASES 1995 – 2015 (TILL 18 JULY), MALAYSIA

10

65

43

14

25

5

19

42

9

27

38

1

10

14

6

71

03

16

36

8 32

76

7

31

54

5

33

89

5

39

65

4

38

55

6

48

84

6

49

33

5

41

48

6

46

17

1

19

88

4

21

90

0

43

34

6

10

86

98

65

39

6

0

20000

40000

60000

80000

100000

1200001

99

5

19

96

19

97

19

98

19

99

20

00

20

01

20

02

20

03

20

04

20

05

20

06

20

07

20

08

20

09

20

10

20

11

20

12

20

13

20

14

20

15

(till

18 J

uly

)

Num

ber

of C

ases

Year

DENGUE DEATHS 1997 – 2015 (TILL 18 JULY) MALAYSIA

11

Jan-18 July 2015 – 65,396 cases with 174 deaths

(compared 48,845 cases with 91 deaths in 2014)

Increase of cases 34% and deaths 91%

CFR 0.26% (target < 0.2%)

DISTRIBUTION OF DENGUE CASES

BY URBAN AND RURAL AREA (1998 – 2014)

13

DENGUE MORTALITY ANALYSIS 2014

(N = 197 DEATHS)

Male

31% : ≥ 50 years old

50% : 25 to 49 years

19% : < 25 years old


(N = 197 DEATHS)

Patients did seek

early treatment:

62% within 48h

after onset

Duration between disease

onset and patients sought 1st

treatment


(N = 197 DEATHS)

Duration in days between

admission & onset of

disease

90% of patients

admitted early to

hospital within 5

days of onset


(N = 197 DEATHS)

Duration between admission and death

ORGAN INVOLVED IN

DENGUE DEATH

Organ involved %

2012

%

2013

%

2014

CNS: Impaired

consciousness 21 33 25

Renal failure 3 33 6

Hepatitis 71 58 59

Multi-organ failure 71 76 59

Heart 29 31 41

18

Dengue Infection

2010

n = 1643

Dengue Infection

2011

n = 798

Dengue Infection

2012

n = 906

Dengue Infection

2013

n=1550

Dengue Infection

2014

n=3261

Age, years

median (IQR) 28.8

(22.5 – 47.3)

29.5

(21.0 – 44.1)

32.8

(21.5-41.8)

31.3

(21.7-46.1)

34.6

(22.0-45.4)

Interval from hospital to

ICU admission, days

median (IQR)

Not available 0.5

(0.1 – 1.3)

0.5

(0.1-1.3)

0.5

(0.1-1.4)

0.4

(0.1-1.2)

Length of ICU stay, days

median (IQR) 1.9

(1.9 – 9.6)

2.0

(1.3 – 3.0)

1.9

(1.2-2.7)

1.9

(1.3-2.9)

2.8

(1.3-3.1)

Length of hospital stay,

days

median (IQR)

5.5

(3.4 – 17.5)

5.8

(4.1 – 8.3)

5.2

(3.9-7.2)

5.3

(3.9-7.2)

7.1

(3.8-7.2)

Length of mechanical

ventilation, days median

(IQR)

3.8

(1.4 – 7.2)

3.6

(1.6 - 7.9)

4.2

(1.0-5.0)

2.9

(1.2-6.2)

5.0

(1.5-6.5)

Total SAPS II score, mean

+/-SD

Median (IQR)

19.0 + 14.1 19.6 + 16.0 17.4 + 13.0 18.6 + 13.2 18.6 + 15.0

15.0 (10.0-23.0)

% Invasive mechanical

ventilation 18.6 13.8 9.5 11.2% 12.1

% Co-morbid diseases 18.1 22.3 18.3 25 22.9

Main organ failure %

Without organ failure 32.2 27.3 35.2 36.3 32.4

Respiratory failure 4.7 3.0 3.3 2.9 5.9

CVS failure 7.1 7.2 6.9 6.1 6.0

Neurological failure 0.6 0.4 0.1 0.7 0.4

Renal failure 0.9 0.7 0.8 1.1 1.2

Hepatic failure 0.4 0.1 0.1 0.3 0.4

Haematological

failure 54.0 40.9 53.4 52.5 53.6

SMR (95% CI) 0.75

(0.42-1.20)

0.50

(0.26- 0.86)

0.51

(0.26- 0.94)

0.50

(0.28-0.95)

0.57

(0.33-1.05)

Severe Dengue in Intensive Care:

Evaluation of Mortality Risk Factors Foong KW1, Teoh SC2, Woon YL3, Lee HS3, Abdul Rahim AH4, Ismail NI5, Kumarasamy S6, Mohd Noor

MR7, Wan Ismail WN8, Kamalul Bahrin LK9, Tong MG10, Vellayuthapillai S2, Supramaniam P3, Tan CC11

Objective: To determine the demography of severe dengue cases in Intensive

Care Unit (ICU) and identify the predictors of mortality

Methods:

• Retrospective study of all adult dengue patients admitted to the 49 MOH

ICUs in year 2013

• Patients were identified via MRIC

• Medical records were reviewed by two intensivists independently to

identify SD patients and determine its onset of critical phase

• Demographic, clinical and intervention data were extracted

• For patients with missing medical record, we assumed those who died

were SD, and relevant data were extracted for mortality patients who

appeared in both MRIC and National Dengue Mortality Enquiry

Report

1531 cases coded as dengue identified from Malaysian Registry of Intensive Care (MRIC)

1436 patients’ medical record traced and screened by 2 intensivists

independently

520 severe dengue

patients identified

95 patients’ medical record missing

916 excluded from analysis: -21 paediatric -188 not dengue -707 not severe dengue

84 patients survived and excluded from analysis

11 patients died (data from MRIC)

527 severe dengue cases analyzed

7 patients with partial data from MRIC and National Dengue Mortality Enquiry Report

4 patients not found in National Dengue

Mortality Enquiry Report and excluded

The flow of patient selection / recruitment



independently

520 severe dengue

patients identified










34.4% of

all dengue

admitted to

ICU



independently

520 severe dengue

patients identified










34.4% of

all dengue

admitted to

ICU

12.7% ie

67 deaths

Table 4: Laboratory results at onset of critical phase / organ dysfunction*

Variables* Estimate Adjusted OR 95% CI

SAPS 0.129 1.137 1.099 – 1.176

Tachycardia 1.111 3.038 1.202 – 7.680

Lethargy 0.988 2.687 1.008 – 7.165

Liver dysfunction 1.173 3.231 1.278 – 8.189

Plasma leakage 1.251 3.493 1.294 – 9.431

Table 5 : Independent risk factors for predicting mortality in severe dengue identified by multivariate logistic regression model

* The variables input in the models are diabetes mellitus, hypertension, breathlessness, dehydration, tachypnoe, oliguria, encephalitis, overbleeding, hematocrit on critical phase, platelet count on critical phase, SAPS II, tachycardia, lethargy, liver dysfunction and plasma leakage. The final model has a R-square of 0.658

Unusual Presentations

of Severe Dengue Fever

Encephalopathy

Hepatic damage

Cardiomyopathy

Severe gastrointestinal

hemorrhage

8 cases



Encephalopathy

Hepatic damage

Cardiomyopathy


hemorrhage

NATURE REVIEWS CARDIOLOGY | REVIEW

Cardiovascular manifestations of the emerging dengue pandemic

Sophie Yacoub, Heiman Wertheim, Cameron P. Simmons, Gavin Screaton

& Bridget Wills

Nature Reviews Cardiology 11,

335–345 (2014) doi:10.1038/nrcardio.2014.40

Published online 08 April 2014

Evidence is increasing that dengue can also cause myocardial impairment, arrhythmias and, occasionally, fulminant myocarditis. Defining the role of cardiac dysfunction in the haemodynamic compromise of severe dengue has potentially important management implications.

http://www.nature.com/nrcardio/journal/v11/n6/abs/nrcardio.2014.40.html













Encephalopathy

Hepatic damage

Cardiomyopathy


hemorrhage

REVISED 2ND EDITION OF 2010 CPG –

2015

THE CHANGES

Calculating weight

Fluid management

Electrolytes and acid-base balance

ECG and ECHO monitoring

Haemophagocytic syndrome

Non-obese and non-overweight patients

Maintenance fluid can be calculated based on the following formula :

- 1.2 - 1.5 ml/kg/hour

Obese and overweight patients

Maintenance fluid can be calculated based on adjusted body weight

Adjusted bodyweight (ABW) can be calculated using this formula. o ABW = IBW + 0.4(actual weight - IBW)* o Ideal bodyweight (IBW) can be estimated based on the following

formula. 72, level III Female: 45.5 kg + 0.91(height -152.4) cm Male: 50.0 kg + 0.91(height -152.4) cm

*Adapted : GlobalRPH 2015, calculator adjusted body weight (available at http://www.globalrph.com/ibw_calc.htm)


2015

THE CHANGES

Calculating weight

Fluid management




ALGORITHM A – FLUID MANAGEMENT IN COMPENSATED SHOCK

COMPENSATED SHOCK (systolic pressure maintained but has signs of reduced perfusion) •Fluid resuscitation with isotonic crystalloid 5 – 10ml/kg/h over 1h •FBC, HCT, before and after fluid resuscitation, BUSEC, LFT, RBS, PT/APTT, Lactate/HCO3, GXM

IMPROVEMENT*

Check HCT

Administer 2nd bolus

of fluid (colloid)**

10 – 20 ml/kg/h for 1h

Consider significant

occult/over bleed

Initiate transfusion with

fresh blood2 (whole

blood/packed cell)

•If patient improves, reduce

to 7-10 ml/kg/h for 1 – 2h

•Then reduce further

•IV crystalloid 5–7ml/kg/h x 1–2h, then:

reduce to 3 – 5 ml/kg/h for 2 – 4h


•If patient continues to improve, fluid

can be further reduced.

•Monitor HCT 4 – 6 hourly

•If the patient is not stable, act

according to HCT levels:

If HCT ↑, consider bolus fluid adminis-

tration or ↑ fluid administration

If HCT decreases, consider

transfusion with fresh whole blood

• Consider to stop IV fluid at 48h of

plasma leakage / defervescence.

* Reassess the patient’s clinical condition, vital signs, pulse volume, capillary refill time, urine output and temperature of extremities.

** Colloid is preferable if the patient has already received previous boluses of crystalloid

IMPROVEMENT*

HCT ↑ or high HCT ↓

NO

NO

YES

YES

•Fluid resuscitation with 20 ml/kg/h colloid 15-30 minutes •Try to obtain a HCT level before fluid resuscitation •FBC, HCT, before and after fluid resuscitation, BUSEC, LFT, RBS, PT/APTT, Lactate/HCO3, GXM

IMPROVEMENT*

Review 1st HCT

Administer 2nd bolus

of fluid (colloid)**

10–20ml/kg ½ to 1h

Consider significant

occult/overt bleed

Initiate transfusion with

fresh blood2 (whole

blood/packed cell)

•Crystalloid/colloid 10ml/kg/hx1h, then

continue with:

IV crystalloid 5 – 7 ml/kg/h for 1 – 2h

reduce to 3 - 5 ml/kg/h for 2 – 4h


•If patient continues to improve, fluid can be

further reduced.

•Monitor HCT q4h or more frequent as

indicated

•If the patient is not stable, act according

to HCT levels :

If HCT ↑, consider bolus fluid adminis-

tration or ↑ fluid administration

If HCT decreases, consider

transfusion with fresh whole blood

Consider to stop IV fluid at 48h of plasma

leakage / defervescence

* Reassess the patient’s clinical condition, vital signs, pulse volume, capillary refill time, urine output and temperature of extremities.

˄ Colloid is preferable if the patient has already received previous boluses of crystalloid

** In absence of colloid, crystalloid can be used

IMPROVEMENT*

HCT ↑ or high HCT ↓

NO

YES

YES

ALGORITHM B – FLUID MANAGEMENT IN DECOMPENSATED SHOCK

HCT Unchanged

REFER

ALGORITHM

C

NO

Repeat 2nd HCT

HCT ↓ HCT ↑ or high

Administer 3rd bolus of fluid

(colloid) 10 – 20 ml/kg over 1h

IMPROVEMENT*

Repeat

3rd HCT NO

YES

ALGORITHM C – FLUID MANAGEMENT IN DECOMPENSATED SHOCK

(WITH PRESENCE OF BLEEDING & LEAKING AND OTHER CAUSES SHOCK)

HAEMATOCRIT REMAIN UNCHANGED AFTER

FIRST FLUID RESUSCITATION

• Bleeding and leaking at same time

• Look for source of bleeding (eg.OGDS)

• Evidence of leaking (USG)

• Correct coagulopathy

• Transfused blood and blood products

Consider other causes of

shock

Cardiac

dysfunction Septic shock Liver failure with

severe metabolic

acidosis from lactate

accumulation

Cytokine

storm

Low CO:

Inotrope

(eg. dobutamine)

High CO:

• Vasodilated shock with

myocardia; dysfunction

• Inotropes + vasopressor

(eg. Noradrenaline +

dobutamine)

• Vasodilated state

• Noradrenaline titrated

to MAP 65 mmHg Vasopressor

+

Supportive care

+

Continuous renal

replacement

therapy (CRRT)

Noradrenaline

and fluids

All the above types of shocks need to be supported by echocardiography and non-invasive cardiac

output monitoring and treatments tailor to each patient.


2015

THE CHANGES

Calculating weight

Fluid management




ELECTROLYTES AND ACID-BASE

BALANCE

Hyponatraemia – common observation in severe dengue

- a marker of disease severity

- underlying mechanism not fully understood

- ? GI loss or ? use of hypotonic solution

Metabolic acidosis - ? Leakage and shock

- consider severe bleeding, liver

failure, sepsis, or cardiac dysfunction


2015

THE CHANGES

Calculating weight

Fluid management




79 patients (adult and children) with dengue infection with 3 severity grades

ECHO exam of intravascular volume + myocardial tissue Doppler Imaging – preload independent of cardiac function parameters

after immediate resus, at 24h and at hospital discharge

Systolic and diastolic impairment with segmental wall abnormalities of the septum and right ventricular wall Least severe dengue – transient More severe dengue – more frequently to have

RECOMMENDATION

• All cases of severe dengue in shock should have Echocardiography to look for evidence of cardiac dysfunction and to guide in fluid management.

• Adequate fluid resuscitation is a pre-requisite before myocardial dysfunction can be diagnosed.

Cautious volume resuscitation is required in those with myocardial dysfunction to avoid risk of iatrogenic fluid overload.


2015

THE CHANGES

Calculating weight

Fluid management




HEMOPHAGOCYTIC SYNDROME

• A potentially fatal hyperinflammatory condition caused by highly stimulated but dysregulated and often ineffective immune responses

• Cardinal features: fever, hepato-splenomegaly, pancytopenia, and widespread histiocytic tissue infiltration

• 2 major forms:

i. primary (hereditary) form - in early childhood ii. secondary (reactive) form - at any age - may be related to infection, malignancy, or autoimmune disease

• Dengue associated haemophagocytic syndrome increasingly reported in case reports and case series in past few years in both primary and secondary dengue infections - South East Asia & among returned travelers from tropical countries.

• Often missed or delayed as its presentation mimics sepsis

DIAGNOSIS

OF HLH Table 2. Proposed HLH diagnostic

criteria, 2009.

1. Molecular diagnosis of hemophagocytic

lymphohistiocytosis

(HLH) or X-linked lymphoproliferative

syndrome (XLP).

2. Or at least 3 of 4:

a. Fever

b. Splenomegaly

c. Cytopenias (minimum 2 cell lines

reduced)

d. Hepatitis

3. And at least 1 of 4:

a. Hemophagocytosis

b. ↑ Ferritin

c. ↑ sIL2Rα (age based)

d. Absent or very decreased NK function

4. Other results supportive of HLH

diagnosis:

a. Hypertriglyceridemia

b. Hypofibrinogenemia

c. Hyponatremia

Limitation:

Retrospective sample – selection bias – medical records, results of bone marrow aspirate, ICD-10 classification

Classification of patients – 4

investigators, independent

Small validation sample – 27 patients compared to 312 patients in development sample

Validated mainly among population

with autoimmune diseases - used with caution in infection associated HS

aROC - 0.97

aROC – 0.95

Goodness of fit 0.93

Goodness of fit 0.76

MANAGEMENT OF HS

Mainly supportive

Not so severe cases can recover spontaneously

Sometimes, short course dexamethasone (10mg/m2 BSA) could be adequate

Due to the transient nature of HS in dengue, full HLH 2004 treatment protocol which includes chemotherapy is not necessary

For severe cases, HS specific therapy i.e IV methylprednisolone + IV Ig – to be tapered off rapidly as patients improve clinically and biochemically

In patients with co-existing sepsis and/or GIT bleeding, risks and benefits on use of steroids need to be weighed

TAKE HOME MESSAGE

Do not forget the basics ie history, physical examination, investigations and diagnosis

Look at the BIG picture – do not fix your mind on one or two parameter

Make a diagnosis after knowing the parameters – more fluids, less fluids, on the right track, other diagnosis, further investigations

Monitor response and medical condition

Remember if you are on the right track, patient should get better

TAKE HOME MESSAGE


Look at the BIG picture – do not fix your mind on one or two parameter/s




TAKE HOME MESSAGE


Look at the BIG picture – do not fix your mind on one or two parameter




ACKNOWLEDGEMENTS

Dr Rose Nani Mudin Public Health Physician (Epidemiologist)

Head of Vector Borne Disease Sector,

Disease Control Division, Ministry of Health Malaysia

Dr Shaharom Nor Azian Che Mat Pengarah, Makmal Kesihatan Awam

Dr Shanthi Ratnam Consultant Intensivist, Hospital Sungai Buloh

Dr Kan Foong Kee Consultant ID, Hospital Sultanah Aminah

THANKS

PEARLS ON SEVERE DENGUE INFECTION

Patient will not have plasma leakage before 72h of

fever. Rise in hematocrit likely means dehydration. Oral rehydration

usually suffices

Transition from febrile phase to critical phase

could be as early as day 3 or as late as day 7 or 8

Critical phase usually 24-48h

Total white cell count (instead of leukopenia) may

increase in patients with severe disease at critical

phase

Liver enzymes are frequently elevated during the

critical and recovery phases

PEARLS ON SEVERE DENGUE INFECTION

Warning sign of severe abdominal pain can be

mistaken as a surgical condition – fever

precedes pain, tender but not guarded, pain

improves with fluid resuscitation

Tense abdomen after IV fluid therapy - due to

ascites + liver congestion can cause abdominal pain -

consider fluid overload instead!

If IV fluid therapy increases, this can cause acute

pulmonary oedema

MANAGEMENT PEARLS OF SEVERE DENGUE

INFECTION

History: Ask open-ended questions • 3 golden questions to ask:

How much oral fluid intake: quantity and quality?

How much urine output: frequency, volume and time of most recent voiding?

What activities can the patient do during the febrile illness?

Examination: “5-in-1 maneuver” magic touch – CCTV-R

Investigations: NS1, IgM, IgG and or PCR

Diagnosis, phase of disease and severity: Does the patient have dengue or other illnesses?

Which phase of dengue (febrile/critical/recovery)?

How severe the disease is? -hydration state? warning signs present? haemodynamic state?

Best medical plan: monitoring

PEARLS ON IV FLUID THERAPY

IV fluid therapy is a Careful Budget of in and out with only one priority ie to maintain tissue perfusion

In outpatient setting, patient should drink enough fluids to pass urine about 4 to 6 times a day

A patient with dengue shock should pass at least 0.5 ml/kg/h urine. If urine volume exceeds 0.5ml/kg/h, consider reducing IV fluid therapy

Remember uncontrolled diabetes or hyperglycemia - shock becomes worse because of glycosuria

Remember changes in haematocrit may be masked by IV fluid therapy

PEARLS ON MONITORING

Monitoring CCTV-R + investigations – Big picture



For severe disease with multi-organ involvement, consider hemophagocytic syndrome

dengue epidemic: what we know so far tan cheng...

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