Severe Dengue: risk factors and management sharing/Severe... · Dengue fever without warning signs (Outpatient Management) • Prevent dehydration: (1) Give plenty of fluids (not

Severe Dengue: risk factors and

management

高雄長庚

李允吉醫師

Outline

• Dengue case management

• Clinical manifestations and risk factors for

severe dengue

• Severe dengue in adults (KSCGMH

preliminary data)

Dengue case management

Dengue: dynamic disease

Compensated shock in the early stage

(normal or elevated blood pressure)

Decompensated shock in the late stages

(hypotension & unrecordable blood pressure)

Fever Warning

signs

Compensated

shock

Hypotensive

shock

Cardiac

arrest

Hours MinHours Hours

Self-limiting disease in most patients.

NOT all patients will experience the critical phase.

Severe disease in a small proportion of patients.

Identification and treatment of early shock will improve clinical outcome.

Risk factors Stable

Patient assessment

In which phase of disease is the patient? Day onset of illness

How much oral fluid intake ?

How much urine output ?

Fluid losses: diarrhea, vomiting

Presence of warning signs

Risk factors: infancy, pregnancy, diabetes mellitus, old age,

renal failure

What was the patient’s pulse volume?

Patient assessment

• Hemodynamic assessment is the foundation of dengue

clinical management

Parameters

Conscious level Organ perfusion (brain)

Capillary refill time

Peripheral perfusionExtremities (color, temp)

Peripheral pulse volume

Heart rate

Cardiac output Pulse pressure

Blood pressure

Respiratory rate Respirator compensation (tissue hypoxia)

Urine output Organ perfusion (kidney)

CCTV-R

1. Skin color

2. Capillary refill

3. Temperature

4. Pulse volume

5. Pulse rate

Patient assessment

Warning signs

1. Abdominal pain or tenderness

2. Persistent vomiting

3. Clinical fluid accumulation

4. Mucosal bleed

5. Lethargy, restlessness

6. Liver enlargement >2 cm

7. Laboratory: increase in HCT concurrent with rapid decrease in platelet count

No

warning

signs

Warning signs and/or co-

existing conditions

1. Pregnancy

2. Infancy

3. Diabetes mellitus

4. Old age

5. Renal failure

1. Severe plasma leakage leading to

shock or fluid accumulation with

respiratory distress

2. Severe bleeding as evaluated by

clinician

3. Severe organ involvement

Outpatient

management

Inpatient

management

Emergency

management

Principle of case management

DON’T use corticosteroids. They are not indicated and can increase the risk of

GI bleeding, hyperglycemia, and immunosuppression.

DON’T give platelet transfusions for a low platelet count. Platelet

transfusions do not decrease the risk of severe bleeding and may instead

lead to fluid overload and prolonged hospitalization.

DON’T give half normal (0.45%) saline. Half normal saline should not be

given, even as a maintenance fluid, because it leaks into third spaces and may

lead to worsening of ascites and pleural effusions.

DON’T assume that IV fluids are necessary. First check if the patient can take

fluids orally. Use only the minimum amount of IV fluid to keep the patient

well-perfused. Decrease IV fluid rate as hemodynamic status improves or

urine output increases.

DON’T give ibuprofen, aspirin, or aspirin-containing drugs, and intramuscular

injection.

Dengue fever without warning signs

(Outpatient Management)

• Prevent dehydration:

(1) Give plenty of fluids (not only water)

(2) Watch for signs of dehydration

▶ Decrease in urination

▶ Few or no tears when child cries

▶ Dry mouth, tongue or lips

▶ Sunken eyes

▶ Listlessness, agitation, or confusion

▶ Fast heartbeat (>100/min)

▶ Cold or clammy fingers and toes

▶ Sunken fontanel in an infant

• Watch for warning signs

Dengue fever with warning signs

(Inpatient Management)

Monitor fluid intake/output

and encourage oral fluid

intake

Obtain baseline complete

blood count

Monitor vital signs every 4

hours

Does patient

have adequate

oral fluid intake?

Adequate oral fluid

intake

Observe for warning

signs and early shock

Inadequate oral fluid

intake


(Inpatient Management)

Inadequate oral fluid

intake

Check HCT

Give isotonic crystalloids in stepwise manner:

1. 5-7ml/kg/h for 1-2 h

2. 3-5ml/kg/h for 2-4 h

Stable and no change or

minimal change in HCTWorsening vital signs

and increasing HCTContinue isotonic

crystalloids: 2-3ml/kg/h

for 2-4 h

Adequate fluid and urine

output (0.5 ml/kg/h); HCT

decreases to baseline.

Stop IVF therapy within

24–48 h

Isotonic crystalloids:

5-10ml/kg/h for 1-2 h

Recheck HCT

Reassess vital signs

Patient improving:

Reduce fluid (stepwise);

reassess before each change

1. 5-10 ml/kg/h for 1-2 h

2. 3-5 ml/kg/h for 2-4 h

3. 2-3 ml/kg/h for 2-4 h

Stop IV fluids at 48 h

Normal saline, Ringer’s lactate

No improved:

Emergency management

Parameters Compensated shock Hypotension shock

Conscious level Clear and lucid Restless

Capillary refill time > 2 sec Very prolonged, mottled

skin

Extremities (color, temp) Cool Cold, clammy

Peripheral pulse volume Weak Feeble, absent

Heart rate Tachycardia Severe tachycardia or

bradycardia in late shock

Blood pressure Normal systolic

pressure, rising diastolic

pressure

Hypotension;

unrecordable BP

Pulse pressure Narrowing, postural

hypotension

≤ 20mmHg

Respiratory rate Tachypnea Kussmaul breathing

Urine output Reduced Oliguria/anuria

How long does plasma leakage last?

24 – 48 hours

Compensated shock

Systolic pressure maintained but has

signs of reduced perfusion

Isotonic crystalloid§5–10 ml/kg/h over 1 h

Hemodynamic status improved Hemodynamic status

not improved (HCT)Reduce fluid (stepwise):

1. 5–7 ml/kg/h for 1–2 h

2. 3–5 ml/kg/h for 2–4 h

3. 2–3 ml/kg/h for 2–4 h

Recheck HCT; reassess

clinical status

If: adequate fluid intake and

urine output; HCT at baseline

or slightly below baseline,

Then: DC intravenous fluids

(stop at 48 hours)

Increasing HCT

Given isotonic

crystalloid10-

20ml/kg bolus 1h

Improving:

Reduce fluid to 7-

10ml/kg/h for 1-2 h

Then reduce further

Obtain HCT and organ

function tests

§Normal saline, Ringer’s

lactate

Decreasing HCT

Initiate transfusion

Hypotensive shock

Obtain HCT and organ function tests

Give 20 ml/kg isotonic crystalloid

or colloid§ over 15 minutes

Hemodynamic status improved Hemodynamic status

not improved Isotonic crystalloid or colloid

infusion at 10 ml/kg/h over 1 h

Reassess clinical status and

HCT; if improving,

reduce fluid in stepwise

manner

1. 5–7 ml/kg/h for 1– 2 h

2. 3–5 ml/kg/h for 2–4 h

3. 2–3 ml/kg/h for 2–4 h

If patient continues to improve,

stop at 48 h

Increasing HCT

Give colloid 10–20

ml/kg over ½ to 1

hour

Improving:

Crystalloid/colloid

10 ml/kg/h for

1 hour, then reduce

fluid

Decreasing HCT

Initiate

transfusionRepeat 2nd HCT

Normal saline, Ringer’s

lactate

§Gelatin-based, dextran-

based and starch-based

solutions

Hematocrit

levels

Increase Decrease NO change (or

minimal

change)

Disease

associated

Plasma leakage 1. Bleeding

2. Reabsorption

Plasma leak +

bleeding

Treatment

related

Blood

transfusion

1. Intravenous

fluid therapy

Disease +

treatment

Plasma leak +

IV fluids

or

Bleeding +

blood

transfusion

Phase of disease, day 2 vs. day 5

Hemodynamic state should be the principal driver of IV fluid therapy

HCT level should only be guide

Rising or high HCT + Unstable hemodynamic state

Active plasma leakage, fluid replacement

Decrease HCT + Unstable hemodynamic state

Bleeding, need for urgent transfusion

Rising or high HCT + Stable hemodynamic state

Does not require intravenous fluid, continue to monitor

Decrease HCT + Stable hemodynamic state

Hemodilution or reabsorption, reduced or DC intravenous fluid

When to start and stop intravenous

fluid therapy

Febrile phase: oral fluid advice

Critical phase: IV fluids are usually required for 24–48 hours

Recovery phase: IV fluids should be stopped so that

extravasated fluids can be reabsorbed

4 Intravenous Fluid Regimens for DSS

in the First Hour

Dextran 70

(n = 55)

Gelatin

(n = 56)

Lactated

Ringer’s

(n = 55)

Normal

saline

(n = 56)

P

“Reshock” rate, no. (%) of

patients

16 (29.1) 15 (26.8) 16 (29.1) 16 (28.6) .992

Decrease in hematocrit at 1 h,

% (mean)

11.5 (3.3) 9.7 (3.0) 5.7 (2.8) 6.5 (2.9) <.001

Decrease in pulse at 1 h,

beats/min (mean)

14.9 (9.9) 18.5 (11.3) 13.2 (9.2) 13.5 (8.9) .023

Total volume of iv fluid

infused, mL/kg (mean)

134.3 (22.1) 135 (23.5) 134.2 (19.9) 132.9 (16.6) 954

Required frusemide, no. (%)

of patients

5 (9.1) 10 (17.9) 8 (14.5) 12 (21.4) .328

Clin Infect Dis 2001; 32:204–13

Three Fluid Solutions for Resuscitation

in DSS

• Kaplan–Meier Curves for Time from Study Entry to Initial (Panel A) and Sustained (Panel B) Cardiovascular Stability among Children in Group 1, According to the Resuscitation Fluid Received.

N Engl J Med 2005; 353;9

Prophylaxis platelet transfusion in

Dengue Fever

• Platelet count, < 20 X 103 /uL

Clin Infect Dis 2009; 48:1262–5

Patients given

platelet transfusion

(n = 188)

Patients not given

platelet transfusion

(n = 68)

P

Age, years 40 (22–64) 39 (22–58) .54

Any bleeding 1 (1) 2 (3) .17

Platelet increment the

next day, x 103

platelets/mL

7(-7 to 50) 11 (-4 to 41) .26

Time to platelet count

≥50 x 103 platelets/mL,

days

3 (1–4) 3 (1–5) .59

Length of hospital stay,

days

6 (4–8) 5 (4–7) .09

Death 1 (1) 0 (0) 1.00

Preventive transfusion in dengue shock

syndrome

• Significant differences in the development of pulmonary

edema and length of hospitalization (P<.05) (in

preventive transfusions group) were observed.

• Preventive transfusions did not produce sustained

improvements in the coagulation status in DSS

J Pediatr. 2003 Nov; 143(5):682-4.

Platelet Transfusion in Dengue Fever

• Acute lung injury after platelet transfusion in a

patient with dengue fever

Asian J Transfus Sci. 2014 Jul-Dec; 8(2): 131–134

Platelet Transfusion in Dengue Fever

• Prophylactic platelet transfusions are not required in

stable patients with platelet count below 20,000/μl.

J Indian Med Assoc. 2011 Jan; 109(1):30-5.

Blood component Indication

Platelet 1. In general there is no need to give prophylactic

platelets even at 20,000/μl.

2. Prophylactic platelet transfusion may be given at

level of <10,000/μl in absence of bleeding

manifestations.

3. Prolonged shock; with coagulopathy.

4. In case of massive bleeding, platelet transfusion

may be needed in addition to red cell transfusion.

Oral Corticosteroid

Therapy in Dengue Infection

• Randomized, Double-Blind Placebo Controlled Trial

Clin Infect Dis 2012;55(9):1216–24

Balapiravir therapy in Dengue

Infection

• Randomized, Double-Blind Placebo Controlled Trial

J Infect Dis 2013;207:1442–50

Chloroquine therapy in Dengue

Infection

• Double-blind, randomized, placebo-controlled trial

PLoS Negl Trop Dis 2010; 4(8): e785

Clinical manifestations and risk factors

for severe dengue

Global dengue burden

Source: From Global Strategy for Dengue Prevention and Control, 2012-2020

全球約25億人口生活在登革熱流行地區，每年發生約5000萬-2億登革熱病例，50萬人住院治療，2.5萬人死亡。

1997 WHO clinical classification of dengue

Dengue virus infection

Asymptomatic Symptomatic

Undifferentiated

fever

Dengue fever

syndromeDengue

hemorrhagic fever

Without

hemorrhage

With unusual

hemorrhage

Without

shock

Dengue shock

syndrome


Dengue

hemorrhagic

fever

Grade

Fever Tourniquet test Increased vascular

permeability

Thrombocytopenia

(<100 000×106

cells/l)

I

Hemorrhagic

manifestations

Rising hematocrit;

hypoproteinemia;

effusion

II

Hypovolemia,

weak pulse,

hypotension

Coagulopathy III (Dengue

shock syndrome)

Severe

bleeding

Profound shock Disseminated

intravascular

coagulopathy

IV (Dengue

shock syndrome)


Severe

dengue

Dengue fever

with warning

signs*

Dengue fever

without

warning signs*

Severe dengue

1. Severe plasma leakage leading to Shock or

fluid accumulation with respiratory distress

2. Severe bleeding as evaluated by clinician

3. Severe organ involvement

• Liver: AST or ALT >=1000

• CNS: Impaired consciousness

• Heart and other organs

Warning signs*

1. Abdominal pain or tenderness


3. Clinical fluid accumulation

4. Mucosal bleed

5. Lethargy, restlessness

6. Liver enlargment >2 cm

7. Laboratory: increase in HCT concurrent with

rapid decrease in platelet count

Source: Dengue guidelines for diagnosis, treatment, prevention and control. Geneva, Switzerland: WHO, 2009

台灣登革熱疫情(1998-20150906)

Source: Taiwan CDC

Rash

Cutaneous hemorrhage

Retinal hemorrhage

Gastrointestinal bleeding

Pleural effusion

Pulmonary congestion and acute

respiratory distress syndrome

Gallbladder swelling

Ascites

Acute abdomen in dengue

Acute abdomen

Acute cholecystitis

Non-specific peritonitis

Acute appendicitis

N=10

Am J Trop Med Hyg 2006; 74: 901

N= 3

N=1

The importance of differential diagnosis in patients with acute abdomen in a dengue-

endemic setting.

Hyperlipasemia and acute pancreatitis in

DHF

• Hyperlipasemia developed in 14 patients with DHF

• Pancreatitis was diagnosed in 3 patients

Pancreas 2007; 35: 381

Spontaneous spleen rupture in DHF

• 29-year-old

female patient

• Conservative

management


Myocarditis in dengue

Int J Infect Dis. 2010 Oct;14(10):e919-22

Rhabdomyolysis in dengue

Am J Trop Med Hyg. 2015 Jan;92(1):75-81

Hemophagocytic Lymphohistiocytosis

MMWR / January 24, 2014 / Vol. 63 / No. 3

Acute transverse myelitis in dengue

J Clin Virol 2006; 35; 312

Concurrent bacteremia in dengue


Bacteria isolated

Klebsiella pneumoniae

Rosemonas spp.

Klebsiella ozaenae

Enterococcus faecalis

Moraxella lacunata

N=1

N=3

Clinicians should be alert to the potential for concurrent bacteremia when treating

patients with DHF/DSS

Case presentation

• 71-year-old woman

• Underlying: Senile dementia, hypertension, chronic

anemia

• Fever and malaise for 5 days

• She was evaluated by her family physician and was

prescribed some medication for a diagnosis of common

cold

• Gum bleeding and gross hematuria were found one

day before presentation at our emergency room

Case presentation

• On examination, the patient appeared clear

consciousness. She was febrile with a temperature of

38°C, pulse rate 100 beats/min, and blood pressure

126/66 mm Hg

• Laboratory data showed leukopenia and

thrombocytopenia

• She living in dengue endemic area; and dengue virus

infection was confirmed by serology test

Case presentation

Day 1 at ER

(day 7 after

illness onset)

Day 2 at ER

(day 8 after

illness onset)

Day 3 at ER

(day 9 after

illness onset)

White blood cell (×109 cells/L) 1.0 1.3 2.1

Hemoglobin g/dL 12.6 12.3 9.8

Hematocrit (%) 36.9 36.6 28.6

Platelet (×109 cells/L) 38 44 42

Creatinine mg/dL 0.71

GOT U/L 263

Platelet

transfusion

24 units

Platelet

transfusion

12 units

Admitted to

ward at night

time

Intravenous fluid: N/S run 60cc/h

(29%)

No more gum bleeding and hematuria

Haemodilution


Case presentation

Day 10 after

illness onset

Day 11 after

illness onset

Day 12 after

illness onset

White blood cell (×109 cells/L) 3.1 4.0 4.0

Hemoglobin g/dL 10.2 10.8 10.5

Hematocrit (%) 30.3 31.1 29.8

Platelet (×109 cells/L) 34 53 70

- The patient became drowsy on the next day after admission (day 10 after illness

onset). On examination she was unconsciousness with cold and clammy

peripheries. Her blood pressure was 60/40 mmHg and with a heart rate of

95/minute. Immediately rapid saline intravenously infusion 1000cc (within 30

minute). Her blood pressure was 110/80 after fluid replacement. Additional fluid

was given 500cc within 1 hour.

- Maintenance intravenous fluid of 60cc/h and monitor hematocrit, platelet count

and I/O.

- Improvement of patient’s consciousness. Reduced intravenous fluid on day 2

after shock.

Case presentation

• Pleural effusion,

ascites and

gallbladder swelling

Case presentation

• Day from onset illness to shock: 10th day

• Plasma leak: pleural effusion, ascites, hemoconcentration

• Critical phase: between 7th and 11th day after onset illness

• Warning signs: mucosal bleeding (gum bleeding, hematuria),

increase hematocrit concurrent decrease platelet count, drowsy

(onset to shock: hours)

Day 7 after

illness onset

Day 17 after

illness onset

White blood cell (×109 cells/L) 1.0 3.0

Hemoglobin g/dL 12.6 9.0

Hematocrit (%) 36.9 26.6

Platelet (×109 cells/L) 38 145

Day

discharge

from

hospital

Hemoconcentration

(39%)

Risk for severe dengue

1. Strain virulence

2. Serotype

Viral

factors

Epidemiological

risk factors

Individual

risk factors

1. Number of

susceptible

2. Vector high

density

3. Wide viral

circulation

4. Hyperendemicity

1. Age

2. Sex

3. Race

4. Nutritional

status

5. Secondary

infection

6. Host

response

Lancet Infectious Disease 2001: 2: 33

Antibody-Dependent

Enhancement

Dengue Fever in the Elderly

Variable Adults (<60y)

n= 6694

Elderly (≥ 60y)

n= 295

P

DHF grade 1-2 1199 (17.9) 80 (27.1) <0.001

DSS 232 (3.5) 6 (2) 0.184

Severe dengue 975 (14.6) 60 (20.3) 0.006

Severe bleeding 401 (41.1) 13 (21.7) 0.003

Severe plasma leakage and organ

involvement

30 (3.1) 10 (16.7) <0.001

Severe bleeding , severe plasma

leakage and organ involvement

13 (1.3) 4 (6.7) 0.014

Pneumonia 36 (0.7) 10 (3.8) <0.001

UTI 17 (0.3) 5 (1.9) 0.003

PLoS Negl Trop Dis 2014: 8(4): e2777

DHF in the Elderly (KSCGMH)

Variable Elderly (≥ 65 years)

(N=66)

Non-elderly (19–64

years) (N=241)

P

Fever, n (%) 60 (90.9) 239 (99.2) 0.002

Bone pain, n (%) 24 (36.4) 147 (61) < 0.001

Acute renal failure, n (%) 8 (12.1) 4 (1.7) 0.001

Concurrent bacteremia, n/N

(%)

4/23 (17.4) 2/59 (3.4) 0.049

Pleural effusion (bilateral or

unilateral), n/N (%)

26/46 (56.5) 60/173 (34.7) 0.010

Gastrointestinal bleeding, n

(%)

21 (32) 47 (19.5) 0.044

Length of hospital stay (day;

mean ± SD)

7.9 ± 4.9 6.3 ± 2.9 0.049

Fatality (%) 5 (7.6) 2 (0.8) 0.006

Am J Trop Med Hyg 2008;79:149

Atypical and more complicated clinical presentation in elderly patients with dengue

In vitro Diabetes’ Mononuclear Cells

Infected with Dengue Virus

Biomed Res Int. 2013;2013:965853

Third post-infection day in an in vitro infection model.

Our result suggest that patients with T2DM are at higher risk for development of

DHF/severe dengue

Diabetes: Risk Factor for Severe

dengue


Warning signs associated with disease

progression

Trop Med Int Health. 2011 Aug;16(8):936-48.

These warning signs were derived in part from a dataset describing 1587 patients

with dengue across Asia and Latin America. Only a small number of subjects (5%)

progressed to severe disease while under observation; several warning signs were

identified.

http://www.ncbi.nlm.nih.gov/pubmed/?term=Multicentre+prospective+study+on+dengue+classification+in+four

Warning signs before severe dengue (n=65)

in adult dengue

• 1. Abdominal pain

• 2. Persistent vomiting

• 3. Hepatomegaly

• 4. Hematocrit rise and

rapid platelet count drop

• 5. Clinical fluid

accumulation

• 6. Mucosal bleeding

• 7. Lethargy

(%)

PLoS Negl Trop Dis 2013; 7(1): e2023.

0

5

10

15

20

25

30

1 2 3 4 5 6 7

15

8

03 2

10

26

Before severe dengue (n=65)

Warning signs for severe dengue (n=248) in

adults

Warning sign SD (n = 248)

Entire clinical course

Abdominal pain or tenderness 109 (44)

Persistent vomiting 41 (16.5)

Hepatomegaly 7 (2.8)

Hematocrit rise and rapid platelet count drop 107 (43.1)

Clinical fluid accumulation 55 (22.2)

Mucosal bleeding 124 (50)

Lethargy 78 (31.5)


Warning signs for predicting severe dengue

in adult dengue

Warning signs Sn Sp PPV NPV

Abdominal pain or tenderness 0.21 0.72 0.09 0.87

Persistent vomiting 0.08 0.93 0.18 0.85

Hepatomegaly 0.00 0.99 0.06 0.84

Hematocrit rise and rapid platelet

count drop

0.05 0.94 0.09 0.89

Clinical fluid accumulation 0.02 0.98 0.16 0.87

Mucosal bleeding 0.17 0.82 0.10 0.89

Lethargy 0.34 0.56 0.17 0.76


Sn = sensitivity, Sp = specificity, PPV = positive predictive value, NPV = negative

predictive value

Onset of warning signs to DHF and severe

dengue in adult dengue

Warning signs Days to severe

dengue

Abdominal pain or tenderness 2 (8–2)

Persistent vomiting 2 (1–5.7)

Hepatomegaly 1.5 (1–2)

Hematocrit rise and rapid platelet count drop 3 (1–7.6)

Clinical fluid accumulation 3 (1–8)

Mucosal bleeding 2 (1–8.5)

Lethargy 3 (1–8)

Warning signs occurred at median of two days before severe dengue


Dengue shock

syndrome in 1719 Vietnamese children

• Shock occurred commonly between days 4 and 6 of illness.

• Warning signs (at the onset of shock):

lethargy (1490/1719 [87%]);

vomiting (1199/1713 [70%]);

abdominal pain (932/1709 [55%]);

liver enlargement (1478/1696 [87%])

• Two-third had bleeding; 31 (2%) patients developed severe bleeding, primarily from the gastrointestinal tract

• 8 patients died; the interval from admission to death was short (median, 34 hours [range, 11–87 hours])

Clin Infect Dis 2013;57(11):1577

Dengue shock

syndrome in 1719 Vietnamese children

• The hematocrit declined rapidly during the first 4 hours of

resuscitation, later rising again in the majority of children.

Clin Infect Dis 2013;57(11):1577

Hours

Factors associated with dengue shock

syndrome: meta-analysis (all ages)

Variable Total sample size

(DSS/DHF)

P Odds ratio (95% CI)

Malnutrition 1689/3449 0.05 1.19 (1.00-1.41)

Neurological signs 859/1891 0.01 4.66 (1.70-12.8)

Vomiting/nausea 839/1891 0.01 1.43 (1.15-1.78)

Abdominal pain 2340/4986 <0.001 2.26 (1.76-2.89)

Gastrointestinal bleeding 786/1317 <0.001 1.84 (1.42-2.39)

Hemoconcentration 2847/5214 <0.001 2.61 (2.02-3.37)

Pleural effusion 1757/3860 <0.001 10.4 (5.47-19.6)

Ascites 373/763 <0.001 5.92 (5.42-14.5)

Hypoalbuminemia 1662/3461 <0.001 4.34 (2.51-7.52)

Hepatomegaly 4130/8906 <0.001 3.10 (2.18-4.41)

Thrombocytopenia (low platelet count) 2801/7172 <0.001 2.08 (1.39-3.12)

Prothrombin time 1661/3713 <0.001 2.83 (1.84-4.37)


Plasma Leakage in Dengue: daily Bedside

Ultrasonography (N=158)

Pediatr Infect Dis J 2007; 26: 283

C-Reactive Protein Levels for Early

Prediction

Median CRP (range)/no, mg/L

Phase of illness Non-severe dengue Severe dengue P

Febrile phase (days 1–3) 14.4 (0.6–69)/87 36.2 (3.3–205.5)/10 0.025

Critical phase (days 4–6) 8 (0.5–215.5)/81 29.2 (6.9–144)/4 0.053

Convalescent phase (days 7–10) 3.3 (1.6–10.7)/8 1.2 (—)/1 -

BioMed Research International 2015; 2015: 936062

In the febrile phase of illness, similarly, a CRP cutoff level of 24.2

mg/L (0.717 AUC) was obtained with 70% sensitivity and 71.3%

specificity for differentiating between non-severe dengue and severe

dengue.

Fatal DHF in adults (Malaysia): clinical

features

Variable Fatal (n=9)

Abdominal pain, N (%) 6 (67)

Vomiting/nausea, N (%) 9 (100)

Lethargy, N (%) 3 (33)

Liver enlargement, N (%) 3 (33)

Any bleeding, N (%) 8 (89)

GI bleeding, N (%) 5 (56)

Ascites, N (%) 5 (56)

Pleural effusion, N (%) 7 (78)

Hypoalbuminemia, n/ N (%) 7/7 (100)

Platelet < 50,000/uL, n/ N (%) 7/7 (100)


2006-2007; 10 fatal cases (median age, 32 years)

The mean duration of illness prior to hospitalization was 4.7 days and

deaths occurred at an average of 2.4 days post-admission.

Fatal DHF in adults (Malaysia): cause of

death

Cause of death No.

DHF 1

DSS 1

DSS with severe GI bleeding and acute renal failure 1

DSS with severe GI bleeding and multi-organ failure 3

DSS with severe GI bleeding 1

DSS with myocarditis and cardiogenic shock 1

DSS with pulmonary edema and sepsis 1


Fatal DHF in adults (Singapore): cause of

death

• 2004; 7 fatal cases

International Journal of Infectious Diseases (2007) 11, 263

Cause of death

Gastrointestinal bleeding; ketoacidosis (DM); multi-organ failure

Myocarditis with cardiogenic shock; ARDS

Gram-negative septicemia; myocarditis with cardiogenic shock; ARDS

Gastrointestinal bleeding; septicemia; multi-organ failure; ARDS

Disseminated intravascular coagulopathy; multi-organ failure

Severe bilateral pneumonia; disseminated intravascular coagulopathy; multi-

organ failure

Acute renal failure; septicemia; ARDS

Fatal Dengue in Adults (KSCGMH)

Variable Fatal (n=10)

Intractable massive GI bleeding with hypovolemic shock, no.

(%)

4 (40%)

DSS alone, no. (%) 2 (20%)

DSS with subarachnoid hemorrhage , no. (%) 1 (10)

Klebsiella pneumoniae bacteremia and meningitis, no. (%) 1 (10)

Sepsis due to mechanical ventilation associated pneumonia, no.

(%)

1 (10)

Enterococcus faecalis bacteremia and intractable massive GI

bleeding with shock, no. (%)

1 (10)

PLoS Negl Trop Dis. 2012;6(2):e1532

Median time lapses :

between dengue onset and hospital presentation, 2 days (1-6);

between hospital presentation to fatality, 4.5 days (2-18 );

between dengue onset to fatality, 7.5 days (4 -21)

Fatal Dengue in Adults (KSCGMH)

Variable

Initial

laboratory data

(fatal group)

(A)

Initial

laboratory data

(non-fatal group)

(B)

Pre-fatal

laboratory data

(48h before

fatality)

(fatal group)

(C)

P

(A vs. B)

P

(C vs. A)

Leukocytosis

(WBC>12000/mL),

n/N (%)

1/10 (10) 4/293 (1.4) 6/9 (66.7) NS 0.020

Bandemia, n/N (%) 3/8 (37.5) 5/277 (1.8) 4/6 (66.7) 0.001 NS

Median platelet

count (mL) (range)

35000 (3000–

157000)

(N = 10)

93000 (1000–

303000)

(N = 299)

17000 (9000–

108000)

(N = 10)

NS <0.001

PLoS Negl Trop Dis. 2012;6(2):e1532

Detection of DENV antigens in tissue

SpleenKidney

HeartLung

Liver

Pathology of fatal dengue (Brazil)

Liver sections of dengue cases,

stained with HE, showing hepatic

injuries, edema (E) and

hemorrhage (He) near central vein

(CV).

PLoS ONE 2014; 9(4): e83386

Lung sections of dengue cases, stained with HE, showing

pulmonary alterations, including septal thickening (St), edema

(E), hemorrhage (He), presence of mononuclear infiltrate (Inf),

hyaline membrane formation (HM) and hypertrophy of alveolar

macrophages (AM) and type II pneumocytes (PcyII)

Pathology of fatal dengue

Heart sections of dengue

cases, stained with HE,

showing hemorrhage (He),

edema (E), presence of

mononuclear infiltrate (Inf)

and degeneration of muscle

fibers (black star).

Kidney sections of dengue


showing hemorrhage (He),

and edema (E)

PLoS ONE 2014; 9(4): e83386

Spleen sections of dengue


showing edema (E)

Severe dengue in adults

(KSCGMH preliminary data)

• Period: 2002 ~ 2014–07

Dengue cases (n=1063)

Age group

No. pat

ient

0

50

100

150

200

250

300

350

18-39 40-49 50-59 60-69 >70

Non-severe dengue

Severe dengue

Incidence of severe dengue:

Age, 18-59 yr (2%) vs. ≥ 60 yr (15%); P<0.001

Based on 2009

WHO dengue

classification

scheme.

55 severe dengue (SD) cases (2009 WHO)

Variable Severe dengue (n = 55)

Median age (range), years 66 (25-85)

≥ 60 years, no. (%) 40 (73)

Male, no. (%) 32 (58.2)

Comorbid condition, no. (%)

Type 2 DM only 1 (1.8)

Hypertension only 9 (16.4)

Type 2 DM and hypertension 10 (18.2)

Type 2 DM, hypertension, and others 6 (11)

Hypertension and chronic kidney disease 2 (3.6)

Chronic kidney disease only 1 (1.8)

G6PD deficiency only 1 (1.8)

DENV serotype, no./No. (%)

DENV 1 5/39 (12.8)

DENV 2 32/39 (82.1)

DENV 3 2/39 (5.1)

DENV 4 0

1997 WHO dengue classification, no. (%)

Dengue fever 5 (9)

Grades 1 and 2 DHF 27 (49)

DSS 23 (41.8)

55% cases had at least one co-morbidity

55 SD cases (2009 WHO)

Variable Severe dengue

Median time from illness onset to hospital presentation

(range), days (n = 55)

3 (1-7)

Median time from illness onset to severe dengue (range),

days (n = 55)

5 (2-10)

Median time from illness onset to shock (range), days (no.)

(n = 23)

6 (2-10)

Median time from hospital presentation to severe dengue

(range), days (n = 55)

1 (1-5)

Median time from hospital presentation to shock (range),

days (no.) (n = 23)

1 (1-5)

Severe dengue in KSCGMH


(n=55)

Non-severe

dengue (n=1008)

P

Mean age (±SD), yrs 63 (13.4) 48.7 (15.5) <0.001

Male, no. (%) 32 (58.2) 464 (46) 0.095

Comorbid condition, no. (%)

Type 2 DM only 1 (1.8) 53 (5.3) 0.520

HTN only 19 (16.4) 110 (11) >0.99

Type 2 DM with HTN 16 (29) 75 (7.4) >0.99

Type 2 DM with HTN and others 6 (11) 16 (1.6) >0.99

G6PD only 1 (1.8) 1 (0.1) >0.99

Dengue virus serotype, no./No. (%)

DENV 1 1/39 (2.6) 12/699 -

DENV 2 32/39 (82.1) 607/699 -

DENV 3 2/39 (5.1) 79/699 -

DENV 4 0 1/699 -

1997 dengue classification, no. (%)

Dengue fever 5 (9) 909 -

DHF, grades 1-2 27 (49) 99 -

DSS 23 (41.8) 0 -

Mean day from onset illness to hospital

presentation (±SD)

3.8 (1.9) 3.7 (2.2) 0.427

Clinical manifestations of dengue


(n=55)

Non-severe

dengue

(n=1008)

P

Symptom/sign at the time of hospital

presentation, no. (%)

Fever 51 (92.7) 955 (94.7) >0.99

Abdominal pain 18 (32.7) 209 (20.7) >0.99

Orbital pain 4 (7.3) 119 (11.8) 0.390

Bone pain 24 (43.6) 436 (43.3) >0.99

Myalgia 27 (49.1) 360 (35.7) >0.99

Headache 20 (36.4) 420 (41.7) 0.484

Vomiting/nausea 25 (45.5) 294 (29.2) >0.99

Diarrhea 10 (18.2) 144 (14.3) >0.99

Petechial 19 (34.5) 229 (22.7) >0.99

Cough 19 (34.5) 256 (25.4) 0.265

Dizziness 10 (18.2) 144 (14.3) >0.99

Gastrointestinal bleeding 31 (56.4) 57 (5.7) <0.001

Laboratory features of dengue

Variable

Severe dengue

(n =55)

Non-severe dengue

(n=1008)

P

Data during the

entire clinical

course

Data at the time of

hospital

presentation

Data at the time of

hospital

presentation

Leukopenia (WBC <3.0 × 109

cells/L), no./ total no. (%)

15/55 (27.3) 6/55 (10.9) 333/977 (34) <0.001

Leukocytosis (WBC >10 ×109 cells/L), no./ total no. (%)

15/55 (27.3) 10/55 (18.2) 3/977 (0.3) <0.001

Mean hematocrit, % (± SD)

(no.)

38.6 (7.4)

(n=55)

36.1 (7.6)

(n=55)

39.3 (5.6)

(n=975)

<0.001

Mean platelet count (± SD)

(× 109 cells/L) (no.)

23.8 (25.3)

(n=55)

56.8 (56.5)

(n=55)

102 (62.1)

(n=984)

<0.001

Severity of thrombocytopenia

Platelet count >150 × 109

cells/L, no./total no. (%)

1/55 (1.8) 7/55 (12.7) 203/984 (20.6) 1

Platelet count 100-149 ×109 cells/L, no./total no. (%)

0 3/55 (5.5) 297/984 (30.2) 0.078

Platelet count 50-99 × 109


5/55 (9.1) 13/55 (23.6) 261/984 (26.5) 0.442

Platelet count <50 × 109


49/55 (89.1) 32/55 (58.2) 223/984 (22.7) 0.001

Laboratory features according to day

onset of illness

SD Day

1-2

(n=14)

Non-SD

Day 1-2

(n=221)

SD Day

3-4

(n=22)

Non-SD

Day 3-4

(n=347)

SD Day

5-7

(n=18)

Non-SD

Day 5-7

(n=376)

Maxi 10.3 10 17.3 19.1 12 17.4

Mini 1.8 1.3 1.8 0.6 1 0.7

Median 4.5 4.2 5.45 3.7 5.95 3.5

0

5

10

15

20

25

White blood cell count

10

9ce

lls/

L

P<0.001P<0.001

P=0.573


onset of illness

SD Day

1-2

(n=14)

Non-SD

Day 1-2

(n=219)

SD Day

3-4

(n=22)

Non-SD

Day 3-4

(n=347)

SD Day

5-7

(n=17)

Non-SD

Day 5-7

(n=372)

Maxi 45.1 49.6 50.4 51 49.9 57.2

Mini 21.9 21.4 24.7 27.8 22.3 23.7

Median 32.9 39.3 38.1 39 36.9 39.8

0

10

20

30

40

50

60

70

Hematocrit

%

P <0.001 P=0.266 P=0.040


onset of illness

SD Day

1-2

(n=14)

Non-SD

Day 1-2

(n=221)

SD Day

3-4

(n=23)

Non-SD

Day 3-4

(n=351)

SD Day

5-7

(n=18)

Non-SD

Day 5-7

(n=379)

Maxi 170 374 190 413.3 191 344

Mini 29 3 1.5 2 3 1

Median 96.5 118 24 102 22 87

0

50

100

150

200

250

300

350

400

450

Platelet count

10

9ce

lls/

L

P=0.260 P<0.001 P<0.001

Severe dengue in KSCGMH

Severe

dengue

n =55

Non-severe

dengue

n = 973

Odds

ratio 95% CI P

Mean age (±SD), yrs 63 (13.4) 48.9 (15.5) 1.071 1.041-1.102 <0.001

Gastrointestinal bleeding,

no. (%)

31 (56.4) 56 (5.7) 12.811 6.549-25.061 <0.001

Leukocytosis (WBC >10

× 109 cells/L), no. (%)

10 (18.2) 3 (0.3) 33.329 4.464-248.838 0.001

Thrombocytopenia <50 ×109 cells/L, no. (%)

32 (58.2) 216 (22.1) 2.181 1.123-4.236 0.021

Parameters

Phase of illness: day 4-7

Host factor

1. Age: Infant (< 1 y/o) and elderly (> 60 y/o)

2. Pregnant

3. Diabetes mellitus

4. Chronic kidney disease

Warning signs

1. Abdominal pain


3. Fluid accumulation

4. Mucosal bleeding (gastrointestinal bleeding)

Evaluation of hemodynamic status: BP CCTV-R

Laboratory data

1. Increase hematocrit concurrent drop platelet count

2. WBC (leukocytosis) and CRP (> 30 mg/L)

Thanks

Severe Dengue: risk factors and management sharing/Severe... · Dengue fever without warning signs (Outpatient Management) • Prevent dehydration: (1) Give plenty of fluids (not

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