Transcript Zika virus syndrome - EAD

Clinical implications of Zika infection
in pregnancy
Ricardo Ximenes
Zika virus syndrome
• Current epidemiological features;
• Timeline of events;
• Major concerns and challenges;
• Ongoing studies;
2015
JAN
FEB
MAR
APR
ZIKV | quadros neurológicos
ZIKV | microcephaly
DENV
MAY
JUN
JUL
2016
AUG
SEP
OCT
NOV
DEC
JAN
FEB
MAR
Microcephaly in Brazil
Aug – Sep
Increased
awareness of
neonates
with
microcephaly
Oct
SES-PE
receives
notifications
from doctors
Oct
Picture
suggestive of
congenital
infection
11th Nov
Declaration of
National Public
Health
Emergency
Oct
Beginning of
investigation
of SES-PE1,
SVS/MS2 and
OPAS
1st Feb
Public Health
Emergency of
International
Concern (PHEIC)
WHO
18 Feb
Notification
of Zika virus
cases –
SINAN Brazil
2016
2015
1 Health
2
Secretary of Pernambuco State
Health Surveillance Secretary of the Ministry of Health
Primary Microcephaly-causes
Causes
Genetic
Environmental
Toxic exposures
Foetal alcohol syndrome
Radiation
Clinical/Infections
TORCH Infections:
Toxoplasmosis,
Other (Syphilis, Varicella-zoster, Parvovirus B19),
Rubella,
Cytomegalovirus (CMV), and
Herpes infections.
Calcifications suggest
infectious origin
Features of Zika congenital infection syndrome
DOI:10.2105/ Miranda et al. American Journal of Public Health - 2016
Zika congenital infection syndrome
microcephaly, arthrogryposis in arms and or legs etc
DENGUE ,
CHIKUNGUNYA, ZIKA E SARAMPO:
PRESENÇA E FREQUÊNCIA DOS PRINCIPAIS SINAIS / SINTOMAS
CHARACTERISTICS
DENV
CHIKUNGUNYA
ZIKV
SARAMPO
Fever
+++++
++++
+
++++
Rash, exanthema
++
++
++++
+++++
Conjunctivitis
+
+
++++
+++++
+++
+++++
++
--
--
++++
+++
--
+++++
+
++
--
Lymphadenopathy
+
++
+
+
Cough
--
--
--
+++
Hemorrhage
++
--
--
--
Hepatomegaly
++
+++
--
+
Leukopenia | Thrombocytopenia
+++
+++
--
+++
Myalgia | Arthralgia
Edema
Retrorbital pain
Obs. Considerar este quadro apenas para auxiliar no diagnóstico clínico em conjunto com outras características clínicas, epidemiológicas e
laboratoriais.
Fonte: Adaptado de Haltead, et al. Departamento de Serviço de Saúdo do Estado de Yap / Micronésia
Issues in the beginning of this outbreak
• Why microcephaly cases were not described during the previous outbreak in French
Polinesia ?
• Eurosurveillance registered similar cases after the Brazilian microcephaly outbreak
• Why so few cases have laboratory confirmation?
•
•
•
•
ZIKV diagnosis by RT-PCR or qRT-PCR
From 30 newborns with microcephaly: ZIKV RNA was not detected (CSF)
Serology was not available, cross-reactivity (DENV1 to DENV4)
The small proportion of laboratory confirmation
Microcephaly by municipality in Pernambuco State,
Brazil – Nov. 2015
Proportion at or below Fenton 3rd percentile
< 0.0001
0.0001 – 0.01
0.01 – 0.02
> 0.02
CASES
BIRTHS
%
August, 2015
10
11,549
0.09
September
30
11,706
0.26
October
115
11,552
1.0
November
239
10,593
2.26
December
158
10,927
1.45
January, 2016
83
11,799
0.70
February
19
10,857
0.18
Microcephaly in live births
Pernambuco State, 1/08/2015 – 12/12/2015
50
45
Confirmed
Cases of Microcephaly
40
35
30
25
14
15
11
10
0
22
18
20
5
23
22
3
1
1
1
0
31
32
33
34
35
5
6
5
5
36
37
38
39
13
11
9
6
40
41
Epidemic week
42
43
44
45
46
47
48
49
Distribution of notifications of suspected cases of
microcephaly in Brazil - Feb 13, 2016
Epidemiology in Brazil (MOH update)
22nd Oct 2015 – 27th Feb 2016
Cases of microcephaly or malformation
suggestive of congenital infections
• 5,909 suspected cases of microcephaly
reported
Total cumulative cases
2015-16
Regions
Investigation
Confirmed
Dismissed
Brazil
4.222
641
1.046
5.909
• 641 (11%) / 5,909 confirmed microcephaly
or suggestive congenital infection
(Pernambuco)
(1.232)
(215)
(225)
(1.672)
• 82 (13%) /642 cases laboratory confirmed
North-East
3.325
625
828
4.778
South-East
477
5
92
574
North
164
3
20
187
Central-West
218
7
89
314
South
38
1
17
56
• 81% reported cases in Northeast
• most in Pernambuco State
http://portalsaude.saude.gov.br/index.php/cidadao
/principal/agencia-saude/22396-saude-investiga-4222-casos-suspeitos-de-microcefalia-no-pais
Confirmed cases of microcephaly
Brazil and elsewhere – 20th Feb 2016
Number of reported
microcephaly cases
Probable location
Reporting country
potentially related to a Zika
of infection
virus infection
French Polynesia
9
French Polynesia
Brazil
583
Brazil
Hawaii (USA)
1
Brazil
Slovenia
1
Brazil
WHO. Zika situation report, 26 February 2016
http://www.who.int/emergencies/zika-virus/situation-report/26-february2016/en/
Diagnosis of Zika virus infection by Serology
 Zika virus (ZIKV) is the first infection by a flavivirus:
- IgM ELISA is specific for zika.
- Plaque reduction neutralization test (PRNT)
shows ≥ 4 fold higher titer to zika virus.
 Zika virus is NOT the first infection by a flavivirus.
- IgM ELISA is not specific; cross-reactivity with other flavivirus may occur.
- PRNT shows titers to many flaviviruses.
- Diagnosis is not possible (equivocal).
ZIKV Detection in Alternative Samples
Result
Specimen
Days after the first symptoms
RT-qPCR
Urine
0 - 18 days
Positive
Saliva
4 – 9 days
Positive
Amniotic fluid
20 weeks
Positive
Breast milk
3 – 20 days
Positive
Semen
4 – 16 days
Positive
Vaginal secretion
3 – 23 days
Negative
Cerebrospinal fluid (CSF)
4 – 9 days
Positive
Submitted to Eurosurveillace
Zika reported cases in all Colombia and by sub-region
to wk 4, 2016
First outbreaks in
the caribbean cost
and northeastern
regions
Zika notifications in Colombia,
1st Oct 2015 –13th Feb 2016
• 37 011 reported cases of clinical Zika
• 1612 laboratory confirmed IgM and/or PCR
• Number of cases per epidemiological week
WHO. Zika situation report, 26 February 2016 http://www.who.int/emergencies/zika-virus/situation-report/26-february-2016/en/
• ZIKV neurotropism:
• ZIKV crosses blood-brain barrier - intraperitoneally injected mice: Dick, 1952
• Progression of disease in directly infected mice brains:
Bell, 1972
• ZIKV cell pathomechanism - autophagy:
• Autophagy: cell-protective mechanism against unwanted material, but:
• ZIKV “hijacks” for viral replication“Virus factories” intracytoplasmatic inclusions
• Pathogenesis of microcephaly – centrosomes:
• Abnormal function & amplification of centrosomes
(mitosis, regulatory functions, vesicle trafficking): Thornton, 2009; Marthiens, 2013
 Microcephaly in fetal ZIKV infection due to ?link autophagy & centromes
Tetro JA. Zika and microcephaly: causation, correlation, or coincidence? Microbes and Infection, Institut Pasteur, 2016, p 1-2.
Medical mystery with a global
reach …
Search to Explain Birth Defects in Brazil Led to
Zika Virus
http://www.nytimes.com/2016/02/07/health/zika-virus-brazil-how-it-spreadexplained.html?_r=0
Evidences
• Occurrence of a new phenotype – Zika congenital syndrome
• Period of major Zika circulation in the North-East of Brazil corresponded to first
gestational months of the mothers
• Nervous system alteration, compatible with infectious disease
• Neurotropism of Zika virus and other Flaviviruses
• Virus detection in amniotic fluid of pregnant women and one still birth
Ayres CF. Lancet Infect Dis. 2016 Feb 4
Publications – online shortly
Positive IgM for ZIKV in CSF of 29 cases of microcephaly in Brazil:
Definitive evidence for a causal link between Zika virus and
microcephaly?
The Lancet 2016 (accepted)
Microcephaly in Pernambuco State –Epidemiological caracteristics and
evaluation of diagnostic criteria
Cadernos de Saude Publica
(Reports in Public Health), 2016
Initial Description of the Presumed Congenital Zika Syndrome.
American Journal of Public
Health, 2016
Head computed tomography findings in infants with congenital
microcephaly due to prenatal Zika virus infection
Submitted 2016 (under review)
The epidemic of Microcephaly in Brazil: description of 104 cases, 2016.
EID, 2016 (accepted)
Final remarks
• Surveillance of Zika, Dengue and Chikungunya cases
• Determine modes of Zika transmission
• Spectrum of the Zika microcephaly syndrome
• Estimate burden, and need for extra healthcare and support
• Adequate control measures
Acknowledgments
MERG Team
Institutions:
Centro de Pesquisas Aggeu Magalhães (Fiocruz Pernambuco)
Universidade Federal de Pernambuco, Recife (UFPE)
Universidade de Pernambuco (UPE), Recife
State Secretariat of Health, Pernambuco
Mother-Child Institute Pernambuco (IMIP) and other state and municipal hospitals
Ministry of Health, Brazil
Pan-American Health Organization, Brazil PAHO, Washington
Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London
Research
MERG Protocols (other publications & updates soon…)
www.cpqam.fiocruz.br/merg/
doi: 10.2105/AJPH.2016.303115
Microcephaly in Infants, Pernambuco State, Brazil, 2015
Table. Characteristics of 104 newborns with microcephaly seen at 2 referral hospitals, Pernambuco State, Brazil, August – December 2015
Finding
Severe microcephaly (%)
Microcephaly (%)
Mother
Gestational age, N=104
At term, (37 wks – 41 wks 6 d)
84
100
Preterm, <37wks
14
0
Postterm, ≥42wks
1
0
60
56
54
47
Calcifications
96
85
Malformation of cortical development, including lissencephaly
71
65
Self-reported rash during pregnancy, n=100
Newborn ǂ
Female sex, N=104
Brain CT scan or MRI, n=58
Emerging Infectious Diseases doi: http://dx.doi.org/10.32032/eid2206.160062
Microcephaly in Infants, Pernambuco State, Brazil, 2015
Table. Characteristics of 104 newborns with microcephaly seen at 2 referral hospitals, Pernambuco State, Brazil, August – December 2015
Finding
Severe microcephaly (%)
Microcephaly (%)
Ventriculomegalia
71
46
Abnormal findings in transfontanellar ultrasound, n=32
100
86
Abnormal findings in fundoscopy, § n=33
28
0
Abnormal findings in OAE, § n=23
12
0
lissencephaly
Emerging Infectious Diseases doi: http://dx.doi.org/10.32032/eid2206.160062
Head computed tomography findings in infants with
congenital microcephaly due to prenatal Zika virus
infection
New England Journal of Medicine
Head computed tomography findings in infants with
congenital microcephaly due to prenatal Zika virus
infection
New England
Journal of Medicine
http://www.fapeg.go.gov.br/conhecimento-para-combater-o-zika/
http://www.who.int/emergencies/zika-virus/situation-report/17-march-2016/en/