Dengue Virus InfectionHKDU seminar

Dr Chan Man Chun, Jacky

Associate Consultant

Department of Medicine and Geriatrics

Princess Margaret Hospital

Outline

• Epidemiology

• Virology

• Aedes Mosquito

• Pathogenesis

• Clinical features

• Laboratory diagnosis

• Management

• Vaccine

HK is surrounded by high risk countries

Kaohsiung 2014 outbreak

6

World figures

Epidemiology

• WHO reports 30x increase in cases since 1960

• No. of countries reporting epidemic dengue has increase > 4x since 1970

• Half the world population are at risk

• ~ 50-100 millions new infections per year

• Case fatality 1-5%

• Worldwide outbreak every 20-40 y

• ~ 75% global population exposed to dengue are in Asia-pacific region

Int J Environ Res Public Health. 2011 Jan;8(1):51-74.

2002 Ma Wan local dengue outbreak

2002 Ma Wan local dengue outbreak

• 20 cases, Aged 20 to 72 yrs., Male: 13

• All Dengue fever

• 16 cases related to Ma Wan construction site (6 residents, 10 CSW)

• Engaged in construction site for the Park Island 珀麗灣

• Onset: early July to 25 September

• All except one, were DEN-1

• In 2001 in Macau, there was a major outbreak of DEN-2 DF of > 1500 cases

• HK strains were different phylogenetically from Macau strains

• One resident (M/17) in Ma Wan donated blood 1/52 before onset of DF

• Recipient: F/72 received RBC from the donor

• Developed fever on 3 days post-transfusion & resolve 4 days later

• blood Test: IgM +ve and IgG HAI titre of 1:2560

Seroprevalence study in HK

• 685 cases from HKRC or researcher collected in 2006

• IgG DV Ab

• Prevalence: 1.6%

Trop Med Int Health 2013;18(9): 1097

Guangzhou cases

HKMJ 2014

2014 Dengue outbreak in HK

• 2 cases also In construction site, but in Sai Ying Pun this time

– 26 Oct 2014: M/63, DEN-1

– 4 Nov 2014: M/25, DEN-1

• 3rd case in Tsing Yi

– 9 Nov 2014: F/35, DEN-4

• All uncomplicated DF

• 2 types of sources

• Risk of endemicity

Dengue virus

• Single stranded Enveloped RNA virus

• Genus Flavivirus

• Arbovirus: transmitted by mosquito

• 4 serotypes: DEN-1, 2, 3, 4

• Same group: Yellow fever virus, Hepatitis C virus, JEV, Tick-borne encephalitis virus

• Infection with one serotype provides lifelong immunity to that virus

• No cross-protective immunity to the other serotypes

Trends in Microbiol 2014;22: 138

1970

2004

Front Immunol 2014;5:290

• Patient becomes infectious 1.5d before onset

• DEN-1 & DEN-2 have longer infectious periods

Vectors

• 2-10mm long

• Flies & feed in daytime other than dusk & dawn

• Short flying range < 200m

• Larval development can occur in < 1 ounce of water (30ml)

• Female also feed on nectar & other sweet plant juice other than blood

• Attracted by CO2 & organic substance produced by host

• Sensitive mosquito, so requiring multiple bites before completion of a full blood meal

• A aegypti transmits Dengue more efficiently than A. albopictus

CDC

✔

Asian Tiger

Aedes. albopictus

Trends in Parasit 2013; 29:460

Life cycle of Aedes

1-2d

1-7d

4d

Total: 5-14d

For A aegypti: 5-7d

For A albopictus: 10-14d

Limitation of Ovitrap:

• Only cover 44 locations in HK

• Aedes has short flying range: 200m. So represent confined region

Aedes in Hong Kong

Why 2nd Dengue infection with a different serotype has a higher chance of having complications

Antibody dependent enhancement

Neutralizing Ab to Dengue 1 virus

Dengue 1 virus

STEP 1- Homologous Ab Form Non-infectious Complexes

Non-neutralizing Ab to Dengue 1 virus

Complex formed by neutralizing Ab and virus

Non-neutralizing Ab to Dengue 1 virus

Dengue 2 virus

STEP2- Heterologous Ab of first serotype infection form Infectious Complexes with second serotype

Complex formed by non-neutralizing Ab and virus

STEP3 - Heterologous Complexes Enter More Monocytes, Where Virus Replicates

Non-neutralizing Ab

Dengue 2 virus

Complex formed by non-neutralizing Ab

& Dengue 2 virus

STEP4 –DHF pathogenesis

N Engl J Med 2012;366:1423-32.

Pathogenesis

Lancet 2014 Sep 12, Epub ahead of print

Classical Clinical Syndromes

1. Undifferentiated fever: most common: > 80%

2. Classical Dengue fever:

– Fever, headache, M & Jt pain, Nausea/vomiting, rash, hemorrhagic manifestation

3. Dengue hemorrhagic fever:

– Fever, hemorrhagic manifestation

– Low platelet < 100

– Evidence of leakage capillaries: Alb, hemotocrit > 20%, Pleural or other effusions

4. Dengue shock syndrome:

– Sign of circulatory failure

Classical Dengue fever

Clinical features of cases in HK

Hong Kong Med J 2008;14:170-7

Clinical features of cases in HK

Symptoms Percentage (N= 124)

Fever 98%

Myalgia 83%

Headache 65%

Skin rash 60%

Fatigue 59%

Dizziness 45%

Retrobulbar pain 34%

GI (nausea, vomiting, diarrhoea) 35%

URT (Dry cough, sore throat) 29%

Epistaxis 10%

Gum bleeding 12%

Hematemesis 2%

Tarry stool 1%

Petechiae 45%

Lymphadenopathy 16%

Laboratory findings Percentage

Thrombocytopenia 86%

Lymphopenia 69%

Neutropenia 78%

Atypical lymphocytes 75%

Prolonged APTT51%

Elevated AST91%

Elevated ALT80%

Hypoalbuminaemia 28%

Clinical course

Reported and estimated DF/ DHF and dengue-2 infections during the 1997

DHF Cuban epidemic

0.067%

1.14%

29%

Of all patientsOf symptomatic

patients

0.23%

4%

Asymptomatic/Mild

Lancet Infectious Diseases 2001; 2: 33–42

New Clinical course

WHO 2012 Handbook for clinical management of dengue

Febrile phase

Critical phase

Clinical pearls

• Leucopenia followed by progressive thrombocytopenia is suggestive of dengue infection.

• Atypical lymphocyte is common in dengue infection

• A rising HCT accompanying progressive thrombocytopenia is critical phase.

• In the absence of a baseline HCT, a HCT > 40% in female & > 46% in male should raise the suspicion of plasma leakage.

• Evidence of increased vascular permeability: pleural effusions, ascites

Laboratory diagnosis

Nature Rev Microbiol 2010; 8:S31

Diagnostic tests

Tests Sensitivity Specificity

IgM test 61.5 – 100% 52 – 100%

IgG test 46.3 – 99% 80 – 100%

Rapid IgM detection 20.5 – 97.7% 76.6% - 90.6%

NS1 Ag detection 54.2 – 93.4% 92.5 – 100%

RT-PCR 59 – 100% 100%

Virus isolation (Cell culture) 40.5% 100%

WHO 2012

WHO 2012

Group A: Sent home

• Criteria:

– Tolerate oral fluid

– No warning signs

– Passing urine regularly

• Treatment:

– Adequate bed rest

– Adequate fluid intake

– PRN paracetamol

• Monitoring:

– Daily review for progression: decrease WBC, fever resolve, warning signs

– Advice to return to hospital if warning signs

Group B: with warning sign or coexisting conditions

• Coexisting conditions: pregnancy, infancy, elderly, DM, CRF

• Social conditions: far from hospital, live alone

• Encourage oral fluid, IV fluid (isotonic solution) if not tolerated

• Adjust fluid requirement based on clinical status & HCT

• Monitoring:

– Vital signs

– Temperature: esp defervescence

– Warning signs

– CBP, HCT

– Urine output

– Organ functions

Group C: Require emergency treatment

• Criteria:

– Severe plasma leakage with shock and/or fluid accumulation with respiratory distress

– Severe bleeding: GIB

– Severe organ impairment

• Management of shock

• Support the organs

• If HCT low (<40% in male, < 45% in female): look for bleeding

• If HCT high (> 50%): continue IV fluid replacement

• Give PC or whole blood for hemorrhagic complication

Criteria for hospital discharge

• Absence of fever for 48 hours

• Improve in clinical status:

– general well-being, appetite,

– hemodynamic status,

– urine output,

– no respiratory distress

• Increasing trend of platelet count

• Stable HCT without IVF

Specific anti-virals for Dengue

XExpert Opin. Ther. 2014;24(11):1171-1184

Vaccines for Dengue virus

N Engl J Med 2007;357:2222

2012

2014

2014

Efficacy of Recombinant live-attenuated tetravalent Dengue vaccines

Year Phase Setting Cases Dose FU Efficacy

2012 2b Thailand4002 cases, 4-11 yo

Injection at 0, 6 & 12 m

25m

Overall: 30.2%DEN-1: 55.6%DEN-2: 9.2%DEN-3: 75.3%DEN-4: 100%

2014 35 Asian countries

10275 cases, 2-14 yo

Injection at 0, 6 & 12 m 25m

Overall: 56.3%DEN-1: 54.5%DEN-2: 34.7%DEN-3: 65.2%DEN-4: 72.4%Vs DHF: 80%Vs severe disease: 70%

2014 35 Latin American countries

20869 cases, 9-16 yo

Injection at 0, 6 & 12 m

25m

Overall: 64.7%DEN-1: 50.3%DEN-2: 42.3%DEN-3: 74%DEN-4: 77.7%Vs severe disease: 95.5%Vs admission: 80.3%

Summary

• > ½ of the world population is at risk for Dengue infection

• No of dengue infections & dengue endemic countries is increasing

• HK is at risk of being dengue endemic

• C/F of dengue is non-specific

• Leucopenia followed by thrombocytopenia with presence of atypical lymphocytes are suggestive

• Antibodies dependent enhancement increases risk of severe dengue diseases in 2nd infection

• NS2 Ag & RT-PCR aid early diagnosis

• Supportive management & organs support are important

• Live-attenuated tetravalent vaccines provide good efficacy

Thanks