Sốt xuất huyết nhũ nhi dengue in infants

Thầy thuốc tận tâmChăm mầm đất nướcMOH, 2016... Thầy thuốc tận tâmChăm mầm đất nước... Thầy thuốc tận tâmChăm mầm đất nướcImmunopathogenesis of Dengue Simmons CP et al.2012... Thầy thuốc

Thầy thuốc tận tâm

Ba điều làm tôi hạnh phúchôm nay!

Thầy thuốc tận tâmChăm mầm đất nước

(MOH, 2016)

Thầy thuốc tận tâmChăm mầm đất nước

Thầy thuốc tận tâmChăm mầm đất nước

Immunopathogenesis of Dengue (Simmons CP et al.(2012) N Engl J

Med 366;15, 1423-1432)

Thầy thuốc tận tâm

Dengue virus infection

The correlation between pathophysiologyand clinical manifestations of DHF

(Hung and Thanh, 2002)

Thầy thuốc tận tâmChăm mầm đất nước

(PAHO, Dengue- Guidelines for patient care in the Region of the Americas, 2016)

Thầy thuốc tận tâm

Chăm mầm đất nước Phân độ nặng Lâm sàng SXHD

Thầy thuốc tận tâmChăm mầm đất nước

Phânbố theo tuổi bệnh nhân SXHD, Việt Nam

(CT SXHQG, 2017)

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Thầy thuốc tận tâm

* Some studies on infants

* Most cases -Secondary infections

* Many studies on the clinical, epidemiological, and immunological aspects.

Understand the immunopathogenesis of Dengue

Study Dengue in infants

LÂM SÀNG SXHNN

As in older children and adults, dengue virus can cause a spectrum of outcomes in infants, ranging from asymptomatic infection to mild or clinically

significant, severe disease

(*WHO, Handbook for clinical management of Dengue, 2012; **PAHO, Dengue- Guidelines for patient care in the Region of the Americas, 2016)

Thầy thuốc tận tâm

Chăm mầm đất nước Clinical manifestations

(WHO, 2012; PAHO, 2016)

High fever, 2–7 days

URT symptoms (cough, nasal congestion, runny nose, dyspnea),

GI symptoms (vomiting, diarrhea).Febrile convulsions

Thầy thuốc tận tâm

Thầy thuốc tận tâmChăm mầm đất nước

Increase in Hct ≥ 20%

The normal value of Hct in infants 2–12 months of

age is relatively low (28–42%) and may be even lower in iron deficiency anemia The mean maximal Hct

values in dengue infants vary from 31.1−40.8%

TDMP / SXH IV, trẻ 11 tháng.

(Hung et al., 2004)

DHF IN INFANTS

95.3% had primary dengue infectionsAge: 6.7  2.5 months (1-11 months)

Đặc điểm xét nghiệm

Tất cả BN SXH không sốc Sốc SXH

Đáp ứng miễn dịch trong SXH Dengue NN

Capture IgM và IgG ELISA

Đáp ứng MD Tất cả BNSXH không sốc Sốc SXH P

Ngày bệnh N3 N4 N5 N6 N7 N8 Tcộng

Sốc ca, 6 45 92 71 30 1 245

% (2,4) (18,3) (37,5) (28,9) (12,2) (0,4) (100)

Phân bố kết quả IgM (+) theo ngày bệnh

79,3% trẻ NN có KT IgM (+) từ ngày thứ 5 trở đi và đáp ứng chéo rất ít với vi rút VN Nhật Bản > Thử

IgM ELISA từ N5 trở đi giúp  + các trường hợp SXHNN.

Đáp ứng MD của các bà mẹ đ/v vi rút Dengue98 trong 99 (98,8%) bà mẹ có đáp ứng HT (+) qua NS1 serotype- specific IgG ELISA:

* 87,8% bà mẹ đã bị nhiễm Dengue  2 lần (đáp ứng kiểu tái nhiễm);

* 12,2 % bị nhiễm 1 lần (đáp ứng kiểu sơ nhiễm)

The sensitivity of diagnostic tests in acute DENV infection of infants

(Chau et al PLoS Negl Trop Dis 2010 Apr 13;4(4):e657)

Cytokine Profile in Infants with DHF/DSS.

Using BD Human Th1/Th2

Cytokine Cytometric BeadArray Kit-II & Flow Cytometry

to determine the plasma levels of

Overproduction of both proinflammatory cytokines (IFN-γ and TNF-α) and anti-inflammatory cytokines (IL-10 and IL-6) may play a role in the pathogenesis of DHF/DSS in infants.

[Hung et al (2004) J of Infectious Diseases, 189:221-232]

Vai trò KT IgG của mẹ truyền qua con qua nhau thai trong sinh bệnh học SXH NN

Mối liên hệ giữa phân phối tuổi trẻ nhũ nhi bị SXH/ SốcSXH và hiệu quả bảo vệ và thúc đẩy nhiễm trùng của

kháng thể từ mẹ (Halstead, Lan et al Emerging Inf Dis,

Dec,2002, 1474-1479) ).

* Severe dengue is less common in infancy but when it does occur the risk of dying is higher than in older children and adults

* Infants with dengue should be referred for in-hospital management (WHO, 2012).

ĐIỀU TRỊ SXHNN

208 trường hợp nhũ nhi

Đặc điểm điều trị SXH NN Tất cả BNSXH không sốcSốc SXH

(n=208)(n=145) (n=63) Lượng dịch TTM110,4 33,6102,1 28,4 P<0,001 129,8 36,9

Tỉ lệ dùng CPT48 (23%) 13 (8,9%) P<0,001 35 (55,5%)

Lượng CPT55,1 25,939,4 16,2 P=0,01 60,9 26,5

Tỉ lệ truyền máu28 (13,4%) 11 (7,5%) P<0,001 17 (26,9%)Lượng máu tươi38,7 32,5 27,3 18,2 P=0,1 44,7 38,1Thời gian TTM(giờ) 25,8 8,825,9 8,1 P=0,5 25,7 10,2

[Hung et al 2006, Am J Trop Med Hyg 72: 370- 374]

(WHO-SEARO, Comprehensive guidelines for prevention and control of dengue and dengue haemorrhagic fever 2011)

Về điều trị sốc SXH NN:

* 55,5% cần truyền CPT, 26,9% cần truyềnmáu>< Trẻ lớn: 22,6- 44,6% cần CPT;

15,6% cần truyền máu [Nimman.1987; Chi

*[Hung et al (2006) Am J Trop Med Hyg.,74(4):684-691]

Average amount of fluid in adults with DSS <= 80 ml/ kg/ 24 hrs [Hien TT, 2005]

Điều trị biến chứng xuất huyết, hạ Natrimáu, và toan hóa máu chuyển hóa

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Rev Cubana Med Trop.1993;45(2):97-101.[Dengue fever and hemorrhagic dengue in

infants with a primary infection]

1

Am J Trop Med Hyg 74(4), 2006, pp 684-691

2

Simmons CP, Chau TN, Thuy TT, Tuan NM, Hoang DM, Thien NT, Lien le B, Quy NT, Hieu NT, Hien TT, McElnea C, Young P, Whitehead S, Hung NT, Farrar J.

J Infect Dis 2007 Aug 1;196(3):416-24 Epub 2007 Jun 19.

birth cohort study of Vietnamese infants.

Chau TN, Hieu NT, Anders KL, Wolbers M, Lien le B, Hieu LT, Hien TT, Hung NT, Farrar J, Whitehead S, Simmons CP.

J Infect Dis 2009 Dec 15;200(12):1893-900

correlate with age-related disease epidemiology, and cellular immune responses correlate with disease severity.

Chau TN, Quyen NT, Thuy TT, Tuan NM, Hoang DM, Dung NT, Lien le B, Quy NT, Hieu NT, Hieu LT, Hien TT, Hung NT, Farrar J, Simmons CP.

J Infect Dis 2008 Aug 15;198(4):516-24.

Chau TN, Anders KL, Lien le B, Hung NT, Hieu LT, Tuan NM, Thuy TT, Phuong le T, Tham NT, Lanh MN, Farrar JJ, Whitehead SS, Simmons CP.PLoS Negl Trop Dis 2010 Apr 13;4(4):e657

Vertical Transmissionand Neonatal Dengue

Dengue & Pregnancy?

The Effects of Dengue on the Pregnancy (WHO, 2012, PAHO, 2016)

- Maternal death from Dengue is infrequently.

- Pregnant women may miscarryor be at risk of miscarriage or prematureduring or up to one month following Dengue infection.

-Fetal growth retardation occurs in a variable proportion of Dengue cases (4-17%) in pregnant women.

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One comparative study that tested 64 umbilical cord serum samples for dengue IgMfrom 63 women who were found to be IgM positive at the time of delivery,

(Tan P et al Obstetrical & Gynecological Survey, 2008, 111:1111–1117.)

Dengue virus can be vertically transmitted to the fetus in utero or to the newborn at parturition

Compare events and pregnancy outcomes between two paired groups of pregnant women: women having presented with

symptomatic dengue during pregnancy (n = 73) and women having had neither fever nor dengue during pregnancy (n = 219) 27% of the women with symptomatic dengue had at least one clinical or biological warning sign These

complications occurred after the 28th week of gestation in 55% of cases

(Basurko C, Everhard S, Matheus S, Restrepo M, HildeÂral H, Lambert V, et al (2018) Aprospective matched study on symptomatic

dengue in pregnancy PLoS ONE 13(10): e0202005).

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• Exposure to dengue during pregnancy was not

significantly associated with prematurity, small for gestational age infants, hypertension or

emergency caesarian section.

• Maternal dengue with warning signs was a risk

factor for peripartum hemorrhage with adjusted relative risk = 8.6 (95% CI = 1.2±62) There was a near significant association between dengue

and in utero death (p = 0.09).

(Basurko C, Everhard S, Matheus S, Restrepo M, HildeÂral H,

Lambert V, et al (2018) Aprospective matched study on symptomaticdengue in pregnancy PLoS ONE 13(10): e0202005).

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• Asymptomatic,

hepatomegaly,

bleeding, circulatory failure, massive intracerebralhemorrhage and death

Clinical manifestations of vertically infected neonates

* Clinical presentation in the newborn infant does not appear to be associated with maternal disease severity or dengue immune status, or mode of

* Timing of maternal infection may be important; peripartum maternal infection may increase the likelihood of symptomatic disease in the newborn

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A review of 17 mother–infant pairs with dengue infection

onset of fever and that of their neonates, were 5–13 days (median, 7 days)

• Fever in neonates occurred at 1–11 days of life(median, 4 days)

• The duration of fever in neonates was 1–5 days(median, 3 days)

(Sirinavin S et al Pediatric Infectious Disease Journal,2004, 23:1042–1047.)

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Antibodies to the dengue virus in the dengue infected mother can cross the placenta and can cause severe dengue in infants

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Management of neonatal dengue

* When a pregnant or parturient woman develops signs consistent with dengue, the diagnosis of

dengue should be considered in her neonate

* Remember that some neonates have become ill as long as 11 days after birth

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Management of neonatal dengue

* The diagnosis of neonatal dengue could eventually be suspected on clinical grounds and then confirmed in the laboratory, but initial presentation may be confused with bacterial sepsis, birth trauma and other causes of neonatal illness.

* Symptomatic and supportive treatment under close observation is the mainstay of treatment.

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Results: 23 patients were reported

≤ 7 days of life: 18 cases> 7 days of life: 5 cases

• There were 16 mothers have fever, and among them, 10 mothers were diagnosed DHFat or near time of

A Study of Neonatal Dengue at Children’s Hospital 2-Ho Chi Minh City, March 2008- June, 2012

(Nguyen Thi Kim Anh, Tran Thi Hoa Phuong, 2016)

The clinical symptoms:

• Others: Jaundice (8 newborns); Poor feeding (5);

Vomiting (4); wheezing (2), cough (10), diarrhea (1)

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• WBC count < 5,000/mm3 : 3 newborns

• Coagulation abnormalities: 5 newborns

• X-ray (n=17): 6 newborns having mild pleural effusion.• Abdominal ultrasound exam (n=17): 6 newborns having

signs of gallbladder wall thickening and intraperitonealfree fluid

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Serology for Dengue of babies:

• IgM(+) and IgG(-): 18 newborns • IgM(+) and IgG(+): 5 newborns.

Serology for Dengue of mothers (17 tested cases):

IgM(+) and IgG(+): 8 mothersIgM(+) and IgG(-): 4 mothers

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The treatment:

* Fluid transfusion: 2 newborns

• Platelet transfusion: 12 newborns

• Frozen fresh plasma transfusion: 4 newborns• Blood transfusion: 1 newborns

Outcome:No death.

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Đặc điểm sốt xuất huyết ở trẻ sơ sinh tại

- 100% bn có tiền sử mẹ được chẩn đoán SXH-D trong giai đoạn chu sinh

- Tuổi bắt đầu sốt là 5 (IQR: 4, 8) ngày sau khi sinh

- Thời gian sốt tổng cộng là 3 (IQR: 2, 4) ngày

• Chẩn đoán ban đầu: NTH SS

• SXH-D: 18,8%, SXH-D cảnh báo: 81,2%

• Chỉ có 6,3% trường hợp được truyền dịch nhằm mục

đích duy trì nhu cầu cơ bản và ngưng truyền trước 24 giờ Chỉ có 1 trường hợp được chỉ định truyền TC vì TC giảm nặng <10000/mm3

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Conclusions

It is difficult to diagnose neonatal DHF early and

differentiate with neonatal sepsis We should suspect of neonatal DHF if the neonate has fever lasting for 3-4 days, thrombocytopenia and good general condition, meanwhile, other investigations for bacterial infections being normal, and maternal history with having DHF at or near time of delivery (Nguyen Thi Kim Anh, Tran Thi Hoa Phuong, 2016; Tuan et al., 2017).

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• Prof Nguyen Trong Lan; Dr Bach Van Cam (Vietnam)• Prof Scott Halstead; Prof Duane J Gubler (USA)

• Prof Suchitra Nimmanitya; Dr Siripen

Kalayanarooj (Thailand)

• Prof Huan-Yao Lei; Prof Ching-Chuan Liu; Dr JH

Huang (Taiwan)

• Colleagues at Children’s Hospital 1 &2; Hospital for

Tropical Diseases; Oxford University Clinical Research Unit (OCRU); Pasteur Institutes- Ho Chi Minh City

Am J Trop Med Hyg., 00(0), 2018, p 1

doi:10.4269/ajtmh.18-0695Copyright © 2018 by The American Society of Tropical Medicine and Hygiene

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