SỐT XUẤT HUYẾT DENGUE- NHỮNG VẤN ĐỀ HIỆN NAY
BS Nguyễn Thanh Hùng Bệnh viện Nhi Đồng 1
TÌNH HÌNH MAÉC SXH KHU VÖÏC PHÍA NAM NAÊM 1998-2006 (DAPCSXHQG)
NAÊM SOÁ MAÉC SOÁ MAÉC/ 100.000 daân SOÁ CHEÁT C/M (%)
347 1998 123997 455,7 0,3
1999 22742 83,6 0,28 65
2000 18740 69,89 0,26 49
2001 28584 104,51 0,25 71
2002 21908 76,6 0,196 43
2003 40543 146,91 0,17 69
2004 66183 207,44 0,16 103
2005 44277 153,1 0,09 47
TB 01 - 05 40907 128,9 0,17 68
2006 65706 201,1 0,09 62
PHAÂN TÍCH CAÙC TRÖÔØNG HÔÏP
TÖÛ VONG 2006
PHAÂN BOÁ SOÁ CA CHEÁT SXH
THEO THAÙNG NAÊM 2006
Soá ca cheát
2004
15
2006
10
2005
Tr.bình 2000-2005
5
0
2
3
4
5
6
7
8
9
10
11
12
1
Thaùng
PHAÂN BOÁ TỬ VONG NĂM 2006 THEO TỈNH 10
9
8
7
6
5
4
3
2
1
0
ĐT
ST, TN
BT, CT, BRVT, ĐN, LĐ, LA, TV, VL
TIỀN GIANG
KIÊN GIANG
BẠC LIÊU
CÀ MAU
AN GIANG
TP. HCM
BD, BP
HẬU GIANG
Phaân boá töû vong theo giôùi
%
70
63.5
60
60
56
54.7
51.3
51.1
48.9
48.7
50
44
42.2
40
36.5
40
30
20
2001 2002 2003 2004 2005 2006
10
0
Nam
Nöõ
Giôùi tính
Phaân boá töû vong theo tuoåi
%
60
48.4
50
44.7
44
40
39.7
40
35.9
33.3
31.3
30
25.6
25.6
25.5
22
20.6
20
20
19
17
16.9
20
12.8
2001 2002 2003 2004 2005 2006
10.9
9.5
7.7
10
6.4
6.3
0
0-04
5-9
10-14
>= 15
Tuoåi
Năm 2006: 93,6% TV ở BN < 15 tuổi; 73% TV ở BN <= 9 tuổi
Phaân boá töû vong theo thôøi gian töø luùc khôûi beänh ñeán töû vong
%
100
76.6
80
73
70
66.7
61.9
60
60
40
29.2
23.8
20
19
2001 2002 2003 2004 2005 2006
17.9
17.9
15.6
20
10.3
9.2
5.1
5
5
4.7
3.2
3.1
1.5
1.2
0
0
<=3
4-6
>=7
Khoâng roõ
Thôøi gian (ngaøy)
Tử vong: N4 -6: 73%; >= N7: 23,8%.
Phaân boá caùc ca töû vong theo thôøi gian töø luùc nhaäp vieän ñeán khi töû vong %
80
71.8
70.3
70
66.7
64.6
64.2
60
40
33.3
31
30.8
25
23.4
20
15.4
2001 2002 2003 2004 2005 2006
12.8
6.3
5
4.8
4.6
0
0
<=2
>=3
Khoâng roõ
Thôøi gian (ngaøy)
Tử vong: <= 2 ngày: 66,7%; >= 3 ngày: 33,3%
Phaân boá ca töû vong theo theo chaån ñoaùn laâm saøng
%
70
58.7
56.4
60
55
52.3
51.6
48.8
47.6
50
44.6
43.6
41.3
40
37.5
40
30
20
2001 2002 2003 2004 2005 2006
9.4
10
5
3.1
2.4
1.5
1.2
0
0
0
0
0
0
0
SXH ñoä II
SXH ñoä III
SXH ñoä IV
Khoâng roõ
Chaån ñoaùn
Sốc SXH: độ III: 58,7%; độ IV: 41,3%
Phaân boá ca töû vong theo theo tuyeán beänh vieän nôi töû vong
%
100
81
78.6
75
80
70.3
66.7
66.2
60
40
26.1
23
21.9
20
2001 2002 2003 2004 2005 2006
20
11.9
11.1
10.3
9.5
7.9
7.8
7.7
5
0
Huyeän
Tænh
Nôi khaùc
Tuyeán beänh vieän
TV tại BV tỉnh: 81%; BV huyện: 7,9%
Phân tích 38 trường hợp tử vong
• Nam/ Nữ: 13/ 25 • Tuổi TB: 7,26 (1-14 t) • 14/ 38 ca ĐT tại BV huyện (cid:1)(cid:1)(cid:1)(cid:1) tỉnh • Tử vong tại BV huyện: 3, BV tỉnh/TW:
35 ca.
• Thời gian điều trị TB: 2,3 ngày (1 giờ- 4
ngày)
Biểu hiện lâm sàng: Tái sốc/SKD: 34 ca Suy hô hấp: 26 ca XHTH: 25 ca T/chứng thần kinh: 10 ca Xét nghiệm: Toan chuyển hóa: 13/ 25 ca DIC: 15/ 18 ca MAC- ELISA: 8/9 ca (+)
Điều trị: Truyền máu: 28 ca, Truyền HT tươi: 6 ca Bù toan: 15 ca CPAP: 24 ca Vận mạch: 25 ca Chọc dò MP/ MB: 11 ca
Đo CVP: 22/ 38 ca; một số ca đo CVP trễ,
thất bại
NGUYÊN NHÂN TỬ VONG
(cid:2)Soác keùo daøi: 29/ 38 ca.
(cid:2)Xuaát huyeát tieâu hoaù naëng: 11/ 38 ca
(cid:2)Suy hoâ haáp: 8/ 38 ca
(cid:2)SXH daïng naõo: 3/ 38 ca
Nhận xét xử trí
• Một số trường hợp chẩn đóan SXH chưa rõ (cid:1)(cid:1)(cid:1)(cid:1) Phải lấy 2 ml máu TM cho HTCĐ, PCR.
• Chưa xử trí tốt ca b/chứng nặng.
• Một số ca xử trí không phù hợp khiến bn
rơi vào SKD.
• Phát hiện trễ XHTH nên chỉ định truyền
máu trễ.
Quaù taûi bn SXH ôû BV huyeän
Quaù taûi bn SXH ôû BV tænh/ BV trung öông
Löôïng giaù hieäu quaû vaø öùng duïng caùc nghieân cöùu (tt)
• Tìm caùc nguyeân nhaân gaây töû vong trong
nhieãm Dengue – Medical audits & khaûo saùt caùc ca töû vong – Autopsy –
• Sinh beänh hoïc (caùc ca töû vong sôùm) • Haäu quaû cuûa ñieàu trò.
Tỉ lệ tử vong SXH các tỉnh phía Nam, 1998-2006 (DAPCSXHQG, 2006)
3
2.47
2.5
2.08
2
% TV sốc SXH
1.53
1.44
1.5
1.24
1.02
1
0.79
0.64
% TV chung
0.55
0.5
0.29
0.28
0.26
0.25
0.196
0.17
0.16
0.09
0.09
0
1998
1999
2000
2001
2002
2003
2004
2005
2006
International Meeting on Dengue, Pune India, Nov 10, 2006
NC tieàn cöùu 8 naêm, Pune, India töø 1998: 2113 bn (Dr Rajesh Gadia): •* XH: 40%, XH naëng: 3%. •* Shock: 7% •* Hoân meâ, daïng naõo: 7% •* Suy gan: 3%, Suy thaän: 2%, DIC: 1% •* ARDS, Phuø phoåi caáp: 4% •Töû vong chung 2%. Giaûm töû vong töø 3,1% naêm 1998 coøn 1,7%. •
Vấn đề chaån ñoùan sôùm nhieãm virus Dengue
Test nhanh phaùt hieän khaùng nguyeân NS1, khaùng theå IgM/ IgG giuùp chaån ñoùan sôùm nhieãm Dengue?
Dengue Diagnostic Panels
Standardize dengue testing worldwide with well defined control serum
GLOBAL PROBLEM GLOBAL PROBLEM
NO VACCINE NO VACCINE
EARLY DIAGNOSIS FOR INTERVENTION EARLY DIAGNOSIS FOR INTERVENTION
Flavivirus Genome (~11Kb)
5‘NCR
3‘NCR
Structural
Nonstructural
CAP
Cotranslational processing
C prM E NS1 2A 2B NS3 NS4A 4B NS5
Pr M
NS1 vs. IgM Rapid Test (Hunsperger E, 2006)
IgG
•NS1 appears earlier than IgM
•NS1 is serotype specific
•NS1 does not persist
NS1
IgM
Viremia
Primary Infection
Secondary Infection
NS1 test in DENFRAME study in Cambodia (Hunsperger E, 2006))
• Patients with dengue clinical symptoms Sensitivity NS1/PCR = 83.3%
PCR + (14% IgM+) 61
PCR – (26% IgM+) 4
65
12
25
NS1 + (15% IgM +) NS1 – (18% IgM +)
37
73 29 102
NS1 test in DENFRAME study in Cambodia (Hunsperger E, 2006)
• Asymptomatic individuals
PCR + (8.3% IgM +)
2
PCR – (13.3% IgM+) 4
6
10
183
NS1 + (50% IgM +) NS1 – (12% IgM+)
193
12 187 199
NS1
• Antigen capture ELISA is sensitive in
ranges of 1-4ng/ml
• Potential correlation between disease
severity and the concentration of antigen in serum (DF vs DHF)
• Commercial kit available through BioRad with sensitivity of 91% (ranging 100% at the 1st day of onset of fever to 35.7% after day 6) and specificity of assay is 100%
Level of NS1 in plasma of dengue infected infants (Cameron et al. in press)
Limit detectable
Kinetics of NS1 and PCR in acute plasma of confirmed dengue cases (Cameron et al. in press)
s e s a c
l
100
80
NS1
PCR
60
40
20
0
e b a t c e t e d f o e g a t n e c r e P
3
4
5
6
7
8
9
10
11
12
13
Day of illness
6 27 64 73 63 42 28 14 2 1 3
No. of cases
Kinetics of NS1, IgM and PCR in acute plasma of confirmed dengue cases (Cameron et al. in press)
s e s a c
120
l
NS1
100
PCR
80
IgM
60
40
20
0
e b a t c e t e d f o e g a t n e c r e P
4
5
6
7
8
9
10 11 12 13
3 Day of illness
6 27 64 73 63 42 28 14 2 1 3
6 19 39 11 1
No. of cases
Vấn đề điều trị
• Ngăn ngừa sốc: Truyền dịch sớm có ngăn ngừa vào sốc và khi nào bắt đầu? (cid:1)(cid:1)(cid:1)(cid:1) Clinical trial?
• Vai troø ñieàu trò buø dòch baèng ñöôøng
uoáng nhaèm giaûm ñoä naëng cuûa nhieãm Dengue.
• Nên dùng lọai dịch gì? • Lượng dịch, tốc độ?
• * Harris E. et al (2003): uoáng nöôùc, nöôùc traùi caây, nöôùc cam trong 24 giôø tröôùc nhaäp vieän giuùp ngöøa nhaäp vieän.
• * Reduced osmolarity oral rehydration
solution (sodium 75 mEq/L, chloride 65 mEq/L, potassium 20 mEq/L, citrate 290 mg/L, glucose or rice powder as carbohydrate)
Current concepts of shock in children (Pediatric Advanced Life Support): in the presence of depleting blood volume, compensatory mechanisms to maintain cardiac output including increased cardiac contractility, tachycardia and increased venous and systemic vasoconstriction can maintain a normal systolic blood pressure.
This status is called compensated shock, which is defined by the presence of systolic blood pressure within the normal range with signs and symptoms of inadequate tissue and organ perfusion.
Decompensated shock is present when signs
of shock are associated with systolic
hypotension.
It is clear that compensated shock in
somewhere between Grade II and III DSS
and that Grade III DSS (hypotension)
identifies late cardiovascular decompensation
(Lucy Lum, 2006)
TRUYEÀN DÒCH TM SXH KHOÂNG SOÁC
• * Loaïi dòch: Normal Saline, RL.
• * Toác ñoä: 6- 7 ml/kg/hr, sau ñoù giaûm
daàn.
• * Dòch trung bình: 80-120 ml/kg/ 24 h.
• * Thôøi gian truyeàn dòch: 24 -48 h.
Löôïng dòch trung bình/ SXH ñoä I, II
Treû nhuõ nhi
Treû lôùn
(n=77)
(n= 145)
105 ± 36,7
102,1 ± 28,4
* Löôïng dòch TB (ml/kg)
20 ± 8,6 giôø
25,9 ± 8,1 giôø
* Thôøi gian truyeàn dòch TB
(Hung et al.
AJTMH, 2006)
Löôïng dòch trung bình/ Soác SXH
Treû lôùn
Treû nhuõ nhi
Người lớn
(n=218)
(n= 63)
121,7 ±38,6
129,8 ±36,9
< 80 ml/ kg/ 24 h
* Löôïng dòch TB (ml/kg)
(TT Hiền et al.)
21 ± 8,1 giôø
25,7 ± 10,2 ø
* Thôøi gian truyeàn dòch TB
(Hung et al. AJTMH, 2006)
Dịch truyền gì tốt nhất cho sốc SXH?
Comparation of three fluid solution
for resuscitation in DSS – Wills B.A. et al (2005) NEJM: 353: 877-89.
• 383 trẻ sốc SXH vừa: LR, Dextran 70 (6%), Hydroxyethyl starch 6%
• 129 trẻ sốc SXH nặng: Dextran 70
(6%), Hydroxyethyl starch 6%
Most children with dengue shock syndrome respond
well to judicious treatment with isotonic crystalloid solutions. Early intervention with colloid solutions is not indicated. The fluid regimen of Ringer’s lactate at 25 ml per kilogram over a period of two hours is now supported by strong prospective evidence and should be recommended for children with moderately severe shock.
For those with severe shock, the situation is less clear- cut, and clinicians must continue to rely on personal experience, familiarity with particular products, local availability, and cost. Minor advantages in initial recovery were shown with starch, and significantly more adverse reactions were associated with dextran, so if the use of a colloid is considered necessary, starch may be the preferred option
RESEARCH & DEVELOPMENT RESEARCH & DEVELOPMENT OF A VACCINE (Barrett A.D. et al., 2006) OF A VACCINE (Barrett A.D. et al., 2006)
RESEARCH & DEVELOPMENT RESEARCH & DEVELOPMENT OF A VACCINE OF A VACCINE
Manufacturing/Regula -tory requirements
Clinical • Phase I: Safety &
• Licensure, scale up,
production, distribution
immunogenicity in small numbers of healthy volunteers.
• Phase II: Safety &
Post licensure • Establishing
recommendations for vaccine use- universal & targeted vaccination.
• Post licensure assessment immunogenicity in several hundred to few thousand volunteers with some assessment of efficacy if possible.
• Phase III: Large
of safety & efficacy (population studies). • Community outreach & education – health professionals and public.
• Cost-effectiveness
multicenter efficacy trial of large number of volunteers at risk of disease. Secondary outcome measures are safety & immunogenicity
Vaccine candidates in Advanced Preclinical Development or Clinical Trials (partial list)
Approach
Developer
Status
DEN genes/antigens
Entire genome
Live, attenuated, produced in PDK cells
Mahidol/Sanofi Pasteur
Phase 2 tetravalent (long- term follow up data up to 8 years)
Sanofi Pasteur
Entire genome
Phase 1
Live attenuated, produced in Vero cells
Entire genome
Phase 2b tetravalent
Live, attenuated, produced in FRhL cells
WRAIR/GSK Biologicals
Entire genome
Phase 1-2 monovalent
Live, rationally attenuated with 3' deletion mutation
US NIAID& Johns Hopkins Univ.
8 DEN4 + 2 chimeric
Phase 1-2 monovalent
Live, 3' deletion mutation, DEN/DEN chimeric
US NIAID & Johns Hopkins Univ.
DNA vaccine
US Navy/WRAIR
2 (prM/E)
Phase 1
US FDA
Live, rationally mutated with 3' point mutations
Entire genome (only DEN2 at present)
Preclinical (non-human primates)
US CDC
Live, attenuated DENV2 vector, DEN/DEN chimeric
8 DEN2 + 2 chimeric (prM/E)
Preclinical (non-human primates)
Phase 2 tetravalent
Live, attenuated YF17D vector, YF/DEN chimeric
Acambis/Sanofi Pasteur
8 YF genes + 2 chimeric DEN genes (prM/E)
Hawaii Biotech
Subunit recombinant antigen, adjuvanted
2 (80%E and DEN2 NS1)
Preclinical (non-human primates)
Conclusions
• No licensed vaccine at present • Effective vaccine must be tetravalent • Field testing of attenuated tetravalent
candidate vaccines is currently underway • Effective, safe and affordable vaccine will not be available in the immediate future • Need research to support implementation of dengue vaccination (i.e., post licensure)
Trang web cuûa beänh vieän Nhi Ñoàng 1, TP Hoà Chí Minh: http://www.nhidong.org.vn
Teân ñaêng nhaäp: bvnhidong Maät khaåu: nhidongbv
