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Dengue Virus InfectionHKDU seminar
Dr Chan Man Chun, Jacky
Associate Consultant
Department of Medicine and Geriatrics
Princess Margaret Hospital
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Outline
• Epidemiology
• Virology
• Aedes Mosquito
• Pathogenesis
• Clinical features
• Laboratory diagnosis
• Management
• Vaccine
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HK is surrounded by high risk countries
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Kaohsiung 2014 outbreak
6
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World figures
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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
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Int J Environ Res Public Health. 2011 Jan;8(1):51-74.
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2002 Ma Wan local dengue outbreak
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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
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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
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Guangzhou cases
HKMJ 2014
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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
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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
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Trends in Microbiol 2014;22: 138
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1970
2004
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Front Immunol 2014;5:290
• Patient becomes infectious 1.5d before onset
• DEN-1 & DEN-2 have longer infectious periods
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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
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Aedes. albopictus
Trends in Parasit 2013; 29:460
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Life cycle of Aedes
1-2d
1-7d
4d
Total: 5-14d
For A aegypti: 5-7d
For A albopictus: 10-14d
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Limitation of Ovitrap:
• Only cover 44 locations in HK
• Aedes has short flying range: 200m. So represent confined region
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Aedes in Hong Kong
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Why 2nd Dengue infection with a different serotype has a higher chance of having complications
Antibody dependent enhancement
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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
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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
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STEP3 - Heterologous Complexes Enter More Monocytes, Where Virus Replicates
Non-neutralizing Ab
Dengue 2 virus
Complex formed by non-neutralizing Ab
& Dengue 2 virus
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STEP4 –DHF pathogenesis
N Engl J Med 2012;366:1423-32.
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Pathogenesis
Lancet 2014 Sep 12, Epub ahead of print
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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
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Classical Dengue fever
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Clinical features of cases in HK
Hong Kong Med J 2008;14:170-7
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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%
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Laboratory findings Percentage
Thrombocytopenia 86%
Lymphopenia 69%
Neutropenia 78%
Atypical lymphocytes 75%
Prolonged APTT51%
Elevated AST91%
Elevated ALT80%
Hypoalbuminaemia 28%
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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
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New Clinical course
WHO 2012 Handbook for clinical management of dengue
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Febrile phase
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Critical phase
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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
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Laboratory diagnosis
Nature Rev Microbiol 2010; 8:S31
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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%
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WHO 2012
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WHO 2012
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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
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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
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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
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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
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Specific anti-virals for Dengue
XExpert Opin. Ther. 2014;24(11):1171-1184
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Vaccines for Dengue virus
N Engl J Med 2007;357:2222
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2012
2014
2014
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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%
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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
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Thanks