el virus zika en brasil: relato de una epidemia · edema mmss e mmii 51 52,9 116 69,5 0 0 167 n...

El virus Zika en Brasil:

Relato de una epidemia

Carlos Brito

Dos linajes: Africano y Asiático

Enfermedad nueva, muchas lagunas en la fisiopatogénesis y en las formas clínicas

Pocos estudios publicados en el mundo

Primer brote importante en 2007: Micronesia (Isla de Yap). Población de 11.241

habitantes

Polinesia Francesa 2013: “cambio de comportamiento "

Brote en la Polinesia Francesa en 2013

Cambio de comportamiento con altas tasas de ataque (sintomáticos en la población

en general) y relatos de aparecimiento de complicaciones neurológicas

Población: 268.270 habitantes

Estimativa de casos: 29.000 casos (Tasa de ataque de 10%).

Casos neurológicos sospechosos (Diagnóstico clínico-epidemiológico)

Número de pacientes asintomáticos: 80% (?????)

(Datos anteriores al cambio de estándares y basado en el trabajo I. Yap)

Virus Zika

ZIKA – EPIDEMIA Y COMPLICACIONES NEUROLÓGICAS

Dic

2014

Diciembre

2014

Enero 2015

Brote de

enfermedad

exantemática

diferente del

dengue

Argumentos: RN-PE

Nuevo estándar:

Un brote de

enfermedad

exantemática de

grandes

proporciones.

“Los especialistas

afirman que no es

compatible con el

dengue" = esto de por

sí supone una

investigación.

• Enfermedad de leve

intensidad

• Rash predominante

• Afebril o subfebril

• Artritogénica

• Conjuntivitis

frecuente

Enero-

Feb-

La Epidemia se

propaga por

varios estados del

Nordeste

Alta diseminación

= vector

E. Artritogénica

diferente del

Chikungunya

Zika ? (Kleber

Luz)

Marzo

SSE=PE

Detecta serología

positiva para el

dengue en casos

con el estándar

clínico de la nueva

enfermedad.

Error de

interpretación:

reacción cruzada

28/04

2015 Secretaria de Saúde Secretaria Executiva de Vigilância em Saúde

Avenida Visconde de Suassuna, 658. Santo Amaro – Recife-PE

Fone: (81) 3355-1893- CEP: 50.050-540

observados anteriormente. Quanto ao grupo etário a maior parte dos casos de dengue no grupo

de entrevistados, são adultos jovens (Tabela 3).

Tabela 2. Sinais e sintomas do grupo de casos de dengue entrevistados, confirmados por

laboratório. Recife, janeiro a abril de 2015 Sinais e sintomas Sim Não Ignorado Total

N % N % N % N

Rash 141 84,4 26 15,6 0 0 167

Prurido 141 84,4 26 15,6 0 0 167

Cefaleia 134 89,7 33 19,8 0 0 167

Artralgia 125 75,0 42 25,1 0 0 167

Mialgia 108 66,2 59 35,3 0 0 167

Febre 128 76,6 39 23,4 0 0 167

Dor retro-orbitária 97 61,8 70 41,9 0 0 167

Astenia/Prostação 95 66,2 72 43,1 0 0 167

Edema MMSS e MMII 51 52,9 116 69,5 0 0 167

Náuseas 49 29,4 118 70,7 0 0 167

Dor abdominal 41 30,9 126 75,4 0 0 167

Diarréia 22 11,8 145 86,8 0 0 167

Conjuntivite 32 36,8 135 80,8 0 0 167

Tabela 3. Casos de dengue entrevistados com confirmação laboratorial, por grupo etário. Recife, janeiro a abril de 2015

Grupo Etário

Secretaria de Saúde Secretaria Executiva de Vigilância em Saúde

Avenida Visconde de Suassuna, 658. Santo Amaro – Recife-PE

Fone: (81) 3355-1893- CEP: 50.050-540

NOTA TÉCNICA - 28 de Abril de 2015

Assunto: Situação da Dengue na Cidade do Recife

Em todo o Brasil, assim como na cidade do Recife, os meses de verão são considerados

historicamente como o período vulnerável para a ocorrência de epidemias de dengue em diversas

cidades do país. Ao longo dos anos, epidemias cíclicas têm sido registradas em todo Brasil.

O Recife encontra-se num cenário de epidemia, e até a semana epidemiológica - SE 16,

foram notificados 6.652 casos de dengue e confirmados 2.234 (33,6%). Em 2014, no mesmo

período, foram notificados 728 casos e confirmados 231, representando um aumento de 813,7%

de casos notificados e 867,5% de casos confirmados.

Em Recife não há transmissão ativa do vírus de Chikungunya com comprovação

laboratorial. Para tanto, tem sido mantida a investigação de todos os possíveis casos suspeitos,

com investigação epidemiológica e laboratorial.

Mediante o cenário do crescimento dos casos prováveis de dengue, foram realizadas no

princípio de Janeiro até o mês de Abril, ações de sensibilização para representantes das unidades

de saúde da rede pública municipal e unidades privadas, com o intuito de chamar atenção da

problemática da dengue, além da importância da notificação oficial de todos os casos suspeitos.

Outras medidas de mobilização social foram intensificadas, assim como na Vigilância

Ambiental e Controle de Endemias: as publicações da portaria para implantar ações de controle

nos finais de semana e feriados do mês de março e abril e da portaria para intervenção em

imóveis fechados pelos agentes de saúde ambiental e controle de endemias.

Dentre os diversos sinais e sintomas referidos nas investigações dos casos suspeitos de

dengue, os mais observados em todas as faixas etárias foram: exantema (pequenas manchas

avermelhadas que estão sendo confundidos com uma intoxicação), prurido (coceira), febre ou

febrícula (muitas vezes não referida), mialgia (dores musculares), cefaleia (dor de cabeça),

prostração, dor retro-orbitária (dor nos olhos). Além disso, muitos casos confirmados por

sorologia apresentaram edema de membros superiores e inferiores e em outras partes do corpo.

Zika Virus in Yap State, Micronesia, 2007

positive specimens. The viral RNA concentrations were

≈900–729,000 copies/mL. Most (15 of 17) of the ZIKV-

positive samples were from specimens collected <3 days

after onset; however, 1 specimen (patient 958) collected on

day 11 after onset was positive with an estimated titer of

≈339,000 copies/mL.

Nucleic Acid Sequence and Phylogenetic Analysis

Several RT-PCR–positive serum specimens were se-

lected, and RNA was amplifi ed by RT-PCR to generate

DNA sequence data for the complete coding region. Be-

cause of limited specimen volume, the complete coding

region genome sequence was only obtainable by combin-

ing sequence data from DNA fragments generated from 4

patients. Thus, the designation EC sequence is used to in-

dicate that the sequence was derived from multiple patients

during the epidemic. The exact contribution of sequence

data from each patient is available upon request. However,

the following points should be noted. Approximately 96%

of the complete coding region was obtained from 3 patients;

sequence data from the fourth patient was used primarily to

fi ll in short gaps in the data. Second, ≈50% of the coding re-

gion data was derived from a complete overlap of data from

>2 patients; in these overlap regions the sequence identity

between different patients was ≈100%. Only 2-nt differ-

ences between patients were noted within the overlapping

regions, strongly suggesting that 1 ZIKV strain circulated

during the epidemic.

Percentage identity over the entire coding region of

ZIKV 2007 EC sequence, when compared with the pro-

totype ZIKV (MR 766, isolated in 1947), was 88.9% and

96.5% at the nucleotide and amino acid levels, respectively.

Phylogenetic trees constructed from the complete coding

region of all available fl aviviruses generated by a variety of

methods (neighbor-joining, maximum-parsimony, or min-

imum-evolution) showed the same overall topology, with

the ZIKV prototype and 2007 EC virus placed in a unique

clade (clade 10) within the mosquito-borne fl avivirus clus-

ter previously described by Kuno et al. (16). Alignment

with phylogenetic tree construction by neighbor-joining,

maximum-parsimony, or minimum-evolution algorithms

was also performed for the NS5 region of all available fl a-

viviruses because extensive sequencing and phylogenetic

analysis have been conducted for this region (16).

Three additional ZIKV strains isolated from Senegal

in 1984 and sequenced in this study were also included in

a tree. This NS5 tree demonstrated similar topology to the

complete coding region tree, with all ZIKVs placed within

a unique clade (clade 10) along with SPOV. Figure 1 shows

the NS5 tree with only mosquito-borne fl aviviruses (clus-

ter) displayed. This NS5 tree also shows that within the

Zika/Spondweni clade there appear to be 3 branches among

ZIKVs: Nigerian ZIKVs, prototype MR766, and 2007 Yap

virus. Percentage identity among these ZIKVs confi rms

the tree topology, in which ZIKV 2007 EC is most distally

related to East and West African ZIKV strains (data not

shown).

The predicted amino acid sequence of ZIKV 2007 EC

contains the Asn-X-Ser/Thr glycosylation motif at posi-

tion 154 in the envelope glycoprotein, found in many fl a-

viviruses, yet absent by deletion in the prototype ZIKV

MR 766. This region of the prototype virus, along with

3 ZIKVs isolated from Senegal in 1984, was sequenced

(Figure 2). Included in this alignment is a ZIKV isolate

from GenBank (accession no. AF372422). Sequencing

confi rmed that prototype ZIKV MR766 has a 4-aa (12-nt)

deletion when compared with ZIKV 2007 EC virus and

ZIKVs from Senegal.

Discussion

Historically, ZIKV has rarely been associated with hu-

man disease, with only 1 small cluster of human cases in

Indonesia reported (9). We report a widespread epidemic

of human disease associated with ZIKV in Yap State in

2007. ZIKV epidemics may have occurred but been mis-

diagnosed as dengue because of similar clinical symptoms

and serologic cross-reactivity with DENVs. Our serologic

data indicate that ZIKV-infected patients can be positive

in an IgM assay for DENVs, particularly if ZIKV is a sec-

ondary fl avivirus infection. If ZIKV is the fi rst fl avivirus

encountered, our data indicate that cross-reactivity is mini-

mal. However, when ZIKV infection occurs after a fl avi-

virus infection, our data indicate that the extent of cross-

reactivity in the IgM assay is greater. Therefore, if ZIKV

infections occur in a population with DENV (or other fl a-

vivirus) background immunity, our data suggest that exten-

sive cross-reactivity in the dengue IgM assay will occur,

which could lead to the erroneous conclusion that dengue

caused the epidemic. Whether this cross-reactivity has oc-

curred is open to speculation. However, reexamination of

specimens from dengue epidemics may provide an answer.

In addition, use of virus isolation or RT-PCR for labora-

tory diagnosis of dengue infections would also prevent this

misinterpretation. Therefore, use of virus detection assays

Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 14, No. 8, August 2008 1237

Figure 2. Alignment of nucleotide and amino acid sequences

adjacent to the envelope (ENV)–154 glycosylation site of Zika virus

strains. Dashes indicate deletions. EC, epidemic consensus.

1321

Zika MR766 1947 Uganda ATGATTGGA------------TATGAAACTGACGAAGATAGAGCG

Zika AF372422 ATGATTGTTAATGAT------------------GAAAACAGAGCA

Zika 41662 Senegal 1984 ATGATTGTGAATGACACAGGACATGAAACTGACGAAAACAGAGCA



Zika 2007 EC Yap ATGATCGTTAATGACACAGGACATGAAACTGATGAGAATAGAGCG

ENV-151 ENV-164

Zika MR766 1947 Uganda MetIleGly------------TyrGluThrAspGluAspArgAla

Zika AF372422 MetIleValAsnAsp------------------GluAsnArgAla

Zika 41662 Senegal 1984 MetIleValAsnAspThrGlyHisGluThrAspGluAsnArgAla



Zika 2007 EC Yap MetIleValAsnAspThrGlyHisGluThrAspGluAsnArgAla

Zika virus (ZIKV) is a mosquito-borne fl avivirus fi rst

isolated in Uganda from a sentinel monkey in 1947. Mos-

quito and sentinel animal surveillance studies have dem-

onstrated that ZIKV is endemic to Africa and Southeast

Asia, yet reported human cases are rare with <10 cases

reported in the literature. In June 2007, an epidemic of fe-

ver and rash associated with ZIKV was detected in Yap

State, Federated States of Micronesia. We report the ge-

netic and serologic properties of the ZIKV associated with

this epidemic.

Zika virus (ZIKV) is a mosquito-transmitted virus in the

family Flaviviridae and genus Flavivirus. It was ini-

tially isolated in 1947 from blood of a febrile sentinel rhe-

sus monkey during a yellow fever study in the Zika forest

of Uganda (1). The virus was subsequently isolated from

a pool of Aedes africanus mosquitoes collected in 1948

from the same region of the Zika forest; a serologic survey

conducted at that time showed that 6.1% of the residents

in nearby regions of Uganda had specifi c antibodies to

ZIKV (1,2).

Over the next 20 years, several ZIKV isolates were

obtained from Aedes spp. in Africa (Ae. africanus) and

Malaysia (Ae. aegypti), implicating these species as likely

epidemic or enzootic vectors (3–5). Several ZIKV human

isolates were also obtained in the 1960s and 1970s from

East and West Africa during routine arbovirus surveillance

studies in the absence of epidemics (6–8). Additional se-

rologic studies in the 1950s and 1960s detected ZIKV in-

fections among humans in Egypt, Nigeria, Uganda, India,

Malaysia, Indonesia, Pakistan, Thailand, North Vietnam,

and the Philippines (5). These data strongly suggest wide-

spread occurrence of ZIKV from Africa to Southeast Asia

west and north of the Wallace line.

In 1977, ZIKV infection was confi rmed among 7 pa-

tients in central Java, Indonesia, during an acute fever study

(9). Data on these 7 ZIKV cases and several previously re-

ported human infections indicated that clinical characteris-

tics of infection with ZIKV included fever, headache, mal-

aise, stomach ache, dizziness, anorexia, and maculopapular

rash; in all cases infection appeared relatively mild, self-

limiting, and nonlethal (6,8–10).

In April 2007, an epidemic of rash, conjunctivitis, and

arthralgia was noted by physicians in Yap State, Federated

States of Micronesia (11). Laboratory testing with a rapid

assay suggested that a dengue virus (DENV) was the caus-

ative agent. In June 2007, samples were sent for confi rma-

tory testing to the Arbovirus Diagnostic Laboratory at the

Centers for Disease Control and Prevention (CDC, Fort

Collins, CO, USA). Serologic testing by immunoglobu-

lin (Ig) M–capture ELISA with DENV antigen confi rmed

recent fl avivirus infection in several patients. Testing by

reverse transcription–PCR (RT-PCR) with fl avivirus con-

sensus primers generated DNA fragments, which when

subjected to nucleic acid sequencing, demonstrated ≈90%

nucleotide identity with ZIKV. These fi ndings indicated

that ZIKV was the causative agent of the Yap epidemic.

We report serologic parameters of the immune response

Genetic and Serologic Properties

of Zika Virus Associated with

an Epidemic, Yap State,

Micronesia, 2007

Robert S. Lanciotti,* Olga L. Kosoy,* Janeen J. Laven,* Jason O. Velez,* Amy J. Lambert,*

Alison J. Johnson,* Stephanie M. Stanfi eld,* and Mark R. Duffy*

RESEARCH

1232 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 14, No. 8, August 2008

*Centers for Disease Control and Prevention, Fort Collins, Colo-

rado, USA

DOI: 10.3201/eid1408.080287

Se confirma la hipótesis de epidemia por Zika en Brasil en abril de 2015

PCR realizado en 8 de un total de 25 muestras de sangre de casos sospechosos de

Bahia (Universidad Federal de Bahia) y

Posteriormente, en 8 de un total de 21 casos de Rio Grande do Norte (Fiocruz/PR).

Virus Zika

database used would require optimization with addition of

reference spectra for the organism and its close relatives

(e.g., B. thailandensis). B. pseudomallei, although differ-

ent from other Burkholderia spp. in its pathogenicity and

epidemiology, is not easily discriminated from B. thailand-

ensis or B. cepacia complex by using phenotypic tests (10).

In summary, infection with B. pseudomallei should be

considered in patients with pneumonia after travel to the

Baja Peninsula in Mexico, and especially after an extreme

weather event. Because of risk for transmission to laborato-

ry workers and the potential for B. pseudomallei to be used

for bioterrorism, clinical laboratories should perform only

limited work up of suspected isolates before referring them

to a public health laboratory for defin

i

tive ident ifica

t

i on.

Acknowledgment

We used the Multi-Locus Sequence Typing website

(http://www.mlst.net) at Imperial College London, developed by

David Aanensen and supported by the Wellcome Trust.

References 1. Currie BJ, Dance DA, Cheng AC. The global distribution of

Burkholderia pseudomallei and meliodosis: an update. Trans R Soc

Trop Med Hyg. 2008;102(Suppl 1):S1–4. http://dx.doi.org/10.1016/

S0035-9203(08)70002-6

2. Inglis TJ, Rolim DB, Sousa AQ. Melioidosis in the Americas.

Am J Trop Med Hyg. 2006;75:947–54.

3. Centers for Disease Control and Prevention. Melioidosis: risk of

exposure, January 26, 2012 [cited 2014 Dec 19]. http://www.cdc.gov/

melioidosis/exposure/index.html

4. Currie BJ. Melioidosis: evolving concepts in epidemiology,

pathogenesis, and treatment. Semin Respir Crit Care Med.

2015;36:111–25. http://dx.doi.org/10.1055/s-0034-1398389

5. Schweizer HP, Limmathurotsakul D, Peacock SJ. New insights

from the 7th World Melioidosis Congress 2013. Emerg Infect Dis.

2014;20:e131737.

6. Wiersinga WJ, Currie BJ, Peacock SJ. Melioidosis. N Engl J Med.

2012;367:1035–44. http://dx.doi.org/10.1056/NEJMra1204699

7. Gee JE, Allender CJ, Tuanvok A, Elrod MG, Hoffmaster AR.

Burkholderia pseudomallei type G in Western Hemisphere.

Emerg Infect Dis. 2014;20:682–4. http://dx.doi.org/10.3201/

eid2004.130960

8. Pitman MC, Luck T, Marshall CS, Anstey NM, Ward L, Currie BJ.

Intravenous therapy duration and outcomes in melioidosis: a new

treatment paradigm. PLoS Negl Trop Dis. 2015;9:e0003586.

http://dx.doi.org/10.1371/journal.pntd.0003586

9. Lipsitz R, Garges S, Aurigemma R, Baccam P, Blaney DD,

Cheng AC, et al. Workshop on treatment of and postexposure

prophylaxis for Burkholderia pseudomallei and B. mallei infection,

2010. Emerg Infect Dis. 2012;18:e2. http://dx.doi.org/10.3201/

eid1812.120638

10. Zong Z, Wang X, Deng Y, Zhou T. Misidentific

a

t ion of

Burkholderia pseudomallei as Burkholderia cepacia by the

Vitek 2 system. J Med Microbiol. 2012;61:1483–4.

http://dx.doi.org/10.1099/jmm.0.041525-0

Address for correspondence: Jennifer W. Cheng, Department of

Infectious Disease, Rush University Medical Center, 600 S Paulina St,

Ste 143, Chicago, IL 60612, USA; email: [email protected]

Zika Virus Outbreak, Bahia, Brazil

Gubio S. Campos, Antonio C. Bandeira,

Silvia I. Sardi

Authors affil

i

at ions: Feder al Un i ver si ty of Bahi a, Sal vador ,

Bahia, Brazil (G.S. Campos, S.I. Sardi); Hospital Aliança, Salvador

(A.C. Bandeira)

DOI: http://dx.doi.org/10.32301/eid2110.150847

To the Editor: Zika virus (ZIKV) is a mosquito-

borne flav i vi rus related to yellow fever virus, dengue virus

(DENV), and West Nile virus (WNV). It is a single-strand-

ed positive RNA virus (10,794-nt genome) that is closely

related to the Spondweni virus and is transmitted by many

Aedes spp. mosquitoes, including Ae. africanus, Ae. lu-

teocephalus, Ae. hensilli, and Ae. aegypti. The virus was

identifie

d

in rhesus monkeys during sylvatic yellow fever

surveillance in the Zika Forest in Uganda in 1947 and was

reported in humans in 1952 (1).

In 2007, an outbreak of ZIKV was reported in Yap Is-

land, Federated States of Micronesia (2). ZIKV also caused

a major epidemic in the French Polynesia in 2013–2014 (3),

and New Caledonia reported imported cases from French

Polynesia in 2013 and reported an outbreak in 2014 (4).

A new challenge has arisen in Brazil with the emer-

gence of ZIKV and co-circulation with others arboviruses

(i.e., DENV and chikungunya virus [CHIKV]). We report

ZIKV infection in Brazil associated with a recent ongoing

outbreak in Camaçari, Bahia, Brazil, of an illness charac-

terized by maculopapular rash, fever, myalgias/arthralgia,

and conjunctivitis.

On March 26, 2015, serum samples were obtained

from 24 patients (Table) at Santa Helena Hospital in Cama-

çari who were given a presumptive diagnosis of an acute

viral illness by emergency department physicians. These

patients were given treatment for a dengue-like illness, and

blood samples were obtained for complete blood counts

and serologic testing by using an ELISA specific for IgG

and IgM against DENV.

Serum samples were analyzed at the Federal Univer-

sity of Bahia by reverse transcription PCR (RT-PCR) to

detect DENV, CHIKV, WNV, Mayaro virus, and ZIKV.

In brief, serum samples were subjected to RNA extrac-

tion by using the QIAamp Viral RNA Mini Kit (QIAGEN,

Hilden, Germany). RNA was reverse transcribed by using

the SuperScript II Reverse Transcription Kit (Invitrogen,

Carlsbad, CA, USA) and subjected to PCRs specific for

DENV (5) CHIKV (6), WNV (7) and Mayaro virus (8).

A positive RT-PCR for a partial region of the envelope

gene with primers ZIKVENF and ZIKVENVR (positions

Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 21, No. 10, October 2015 1885

LETTERS















i

tive ident ifica

t

i on.

Acknowledgment







S0035-9203(08)70002-6


Am J Trop Med Hyg. 2006;75:947–54.






2015;36:111–25. http://dx.doi.org/10.1055/s-0034-1398389



2014;20:e131737.






eid2004.130960









eid1812.120638


a

t ion of









Silvia I. Sardi

Authors affil

i



(A.C. Bandeira)









identifie

d















and conjunctivitis.





















LETTERS

Caso sospechoso:

Aquellos que presentan evidencias clínicas y epidemiológicas (con antecedentes recientes, proceden del área con casos confirmados, endémicos o epidémicos). Ej: Dengue, Zika, Chikungunya.

Caso confirmado por laboratorio:

Cualquier caso sospechoso confirmado por exámenes específicos.

Caso confirmado por Criterio clínico-epidemiológico:

Durante el brote de los primeros casos, todos los esfuerzos deben concentrarse para asegurar el diagnóstico laboratorial. Sin embargo, una vez declarada la transmisión, no todos los pacientes necesitarán la confirmación laboratorial.

El caso podrá ser notificado (confirmado), como el de la infección sospechosa, con base en criterios clínicos-epidemiológicos.

Reservar las pruebas de laboratorio, en este contexto, para los casos graves o con cuadros atípicos.

DEFINICIÓN DE CASOS - NOTIFICACIÓN

Carlos Brito UFPE

Definición: Pacientes que presenten:

Ausencia de fiebre o fiebre, medida o referida, hasta 38,5°C E, exantema máculopapular pruriginoso que aparece dentro de las 72 horas posteriores a los primeiros síntomas, acompañado de por lo menos UNO de los siguientes signos y síntomas:

Hiperemia conjuntival no purulenta (ojos rojos) O

Artralgia O

Edema en miembros

con antecedente epidemiológico positivo

Diferencial: Dengue, Chikungunya, Sarampión y Rubeola principalmente.

Definición del caso Zika:

Exantema máculopapular pruriginoso que ocurre 72 horas despúes de los primeros síntomas, sin fiebre o fiebre referida o fiebre medida ≤ 38,5 C E, pudiendo presentar los siguientes signos y síntomas:

Hiperemia conjuntival (no purulenta)

Artralgia

Edema articular

DEFINICIÓN DE CASOS - ZIKA

• Estudio de base hospitalaria, descriptivo, serie de casos

Periodo de estudio

De enero a julio de 2015

Fuente de datos

• Historia clínica de la emergencia

Lugar de estudio

Hospital Santa Joana (Privado-Referencia en la atención

de emergencias del polo médico de Recife)

Investigación Dengue-Zika – Unidad de Emergencia

Carlos Brito UFPE

Resultados preliminares

Historias clínicas analizadas 335 (T: 900) Total: 900

Excluidos 1 1

Inconcluyente, faltan

datos/síntomas

49 Faltan datos (No figura el tiempo de

enfermedad o de rash)

Duplicidad 30 Más de una atención

N=802

Diagnóstico Zika Dengue Inconcluyente Otros N 585 101 25 11

% 81% 14% 3% 2%

Pérdidas: 6,23%

73

164

303

182

Jan Fev Março Abril

N casos/mes

Variable n (%)

Sexo femenino 354 (60,5)

Mediana (Intervalo)

Edad (años) 31 (5m - 79)

Rango de edad n (%)

0 – 14 años 149 (25,5)

15 – 49 años 344 (58,8)

> 50 años 92 (15,7)

Casos Zika N=585

Rango de edad N %

0-4 71 12,1

5-9 A 42 7,2

10-14 A 36 6,2

15-19 A 38 6,5

20-39 A 237 40,5

40-59 125 21,4

>60 A 36 6,2

Total 585 100,0

Carlos Brito UFPE

Variable Mediana (Intervalo)

Fecha IS - 1ª Atención (días) 2 (8h – 7)

Fiebre en la 1ª atención n (%)

Fiebre referida/medida 73 (30)

Fiebre>38,5 2 (2,7)

N=244

Resultados preliminares

292

173 179 166

143

72

29 16 15 13 10 12

0

50

100

150

200

250

300

350 Síntoma 585

Prurito 49,9

Cefalea 29,6

Mialgia 30,6

Astenia 28,4

Artralgia 24,4

Dolor retro-orbitario 12,3

Edema articulaciones 5,0

Adenomegalia 2,7

Conjuntivitis 2,6

Dolor de garganta 2,2

Diarrea 1,7

Vómitos 2,1

DIAGNÓSTICO DIFERENCIAL DE DENGUE, ZIKA Y CHIKUNGUNYA

Exantema Aparece a partir del

cuarto día Aparece en el primer o

segundo día Aparece 2-5 día

30-50% de los casos 90-100% de los casos

Frecuencia 50% de los casos

Aspectos Clínico/Laboratorial

Dengue Zika Chikungunya

Fiebre/estándares Más de 38°C Sin fiebre o subfebril

(≤ 38,5°C) Fiebre alta > 38°C

Alta (Varias x/día) Fiebre leve (1-2x/día) Alta en 1-2 día

Duración 4 a 7 días 1-2 días 2-3 días

Mialgia (Frecuencia)

+++ ++ +

Artralgia (frecuencia)

+ ++ +++

Intensidad del dolor articular

Leve Leve/Moderado Moderado/Severo

Edema articulaciones Raro Frecuente, leve intensidad Frecuente, moderado a severo Conjuntivitis Raro 50-90% de los casos 30%

Cefalea +++ ++ ++

Hipertrofia ganglionar + +++ ++

Discrasia sanguínea ++ ausente +

Riesgo de muerte Existe (+++) Existe (?)* Existe (+)

Complicación Neurológica ++ +++ (?) + (predominante en Neonatos)

Leucopenia +++ +++ +++

Linfopenia Infrecuente Infrecuente Frecuente

Trombocitopenia +++ Ausente +

ZIKA – EPIDEMIA Y COMPLICACIONES NEUROLÓGICAS

Dic

2014

Diciembre

2014/

Enero 2015

Brote

enfermedad

exantemática

diferente del

dengue

Argumentos: RN-PE

Nuevos estándares:

Un brote de E.

exantemática de

grandes

proporciones.


afirman que no es

compatible con el

dengue" = esto de por

sí supone una

investigación.

• Enfermedad de leve

intensidad

• Rash predominante

• Afebril o subfebril

• Artritogénica

• Conjuntivitis

frecuente

Enero-

Feb-

Aumento de casos

neurológicos (RN,

PE, BA)

Pernambuco

Emitimos un alerta a los

neurólogos, via

whatsApp, sobre el

riesgo de aumento de

los casos neurológicos

Dr. Iris Machado / Dra.

Lucia Brito - HR

(contestan

positivamente)

15 mayo

2015

En visita al HR:

Gran número de

casos, superior a

los años

anteriores.

Entrevisto a los

pacientes: “Cuadro

clinico viral,

antecedente de

Zika"

Hipótesis de la

Polinesia Francesa

se confirma

FIOCRUZ-PE

(LAVITE)

Confirma 7 casos

neurológicos por

PCR y aislamiento

viral Zika +

Junio

2015

Nuevo

aumento de

los casos

neurológicos

en diciembre

de 2015

Nov/Dic

2015

Número de casos

con aumento

progresivo

Mayo/junio

2015

La epidemia se

propaga por

varios estados del

Nordeste

Alta diseminación

= vector

E. Artritogénica

diferente del

Chikungunya

Zika ? (Kleber

Luz)

Marzo















i

tive ident ifica

t

i on.

Acknowledgment







S0035-9203(08)70002-6


Am J Trop Med Hyg. 2006;75:947–54.






2015;36:111–25. http://dx.doi.org/10.1055/s-0034-1398389



2014;20:e131737.






eid2004.130960









eid1812.120638


a

t ion of









Silvia I. Sardi

Authors affil

i



(A.C. Bandeira)









identifie

d















and conjunctivitis.





















LETTERS















i

tive ident ifica

t

i on.

Acknowledgment







S0035-9203(08)70002-6


Am J Trop Med Hyg. 2006;75:947–54.






2015;36:111–25. http://dx.doi.org/10.1055/s-0034-1398389



2014;20:e131737.






eid2004.130960









eid1812.120638


a

t ion of









Silvia I. Sardi

Authors affil

i



(A.C. Bandeira)









identifie

d















and conjunctivitis.





















LETTERS

8/25 muestras BA

(Campos G)

8/21 muestras RN

(Zanluca C)

Abril

2015

NEUROTROPISMO

Noviembre de 2013 y febrero de 2014: 72 casos de

complicaciones neurológicas (Cinco en el año anterior)

Antecedente de infecciones compatibles con el Zika

42 casos de síndrome de Guillain-Barré (SGB)

Ioss S. Medecine et maladies infectieuses 44 (2014) 302–307

Dick GW, et al (1952). Estudio en modelo animal-Zika:

La inoculación de algunos ratones demostró debilidad motora, paralisis de los miembros y

muerte posterior; sin embargo, eventualmente, algunos se recuperaron.

Se analizaron los riñones, pulmones, hígado, bazo y cerebro de los ratones.

En ningún otro órgano, fuera el cerebro, el vírus se encuentra presente en cantidades

demostrables.

Edemas generalizados fueron observados en los cerebros de algunos ratones;

degeneración neuronal e infiltración celular también fueron detectados.

Carlos Brito UFPE

CASOS NEUROLÓGICOS CONFIRMADOS EN PERNAMBUCO LCR Y SUERO LAVITE - LABORATORIO DE VIROLOGÍA Y TERAPIA EXPERIMENTAL (FIOCRUZ-PE)

01 caso meningoencefalitis 90 casos en investigación (LCR y suero almacenados)

Apenas 01 caso sin rash (Fiebre+artralgia+edema) Tiempo entre la enfermedad y la alteración neurológica: 3-13 días PCR positivo en muestras tardías

Cuadro neurológico

posterior

Zika (días)

Tiempo entre CV y

muestra positiva PCR

7 27

5 25

5 34

3 27

13 15

4 31

Iniciales

Diagnósticos

Tratamiento

Evolución Inmediata

Evolución despúes de 3 meses

MCSXS ADEM (NMO like) MTP + IGIV incompleta secuela motora MMII y visual bilateral

GGS SGB IGIV incompleta secuela motora en MMII

ACSL SGB IGIV completa

EBS SGB IGIV incompleta secuela motora en los cuatro miembros

MLGS ADEM MTP incompleta secuela motora en los cuatro miembros y declive cognitivo

JLBA SGB IGIV incompleta secuela motora en los cuatro miembros

Leyenda: SGB – Síndrome de Guillain-Barré NMO like: similar a neuromielitis óptica IGIV: inmunoglobulina intravenosa

ADEM: encefalomielitis aguda diseminada MTP: metilprednisolona intravenosa MMII: miembros inferiores

06 pacientes

PCR-Zika positivo: 04 en sangre y 06 en orina

Orina con carga viral más elevada que en las muestras de suero

Las muestras de orina dieron positivo más de 20 días despúes que la viremia

alcanzó un nivel indetectable

Conclusión: ZIKV ARN es detectable en la orina, con una carga más elevada y

con una mayor duración que en el suero.

Muestra Ministerio de Salud de Brasil – EPISUS Alteraciones neurológicas - Pernambuco

Características generales de los casos de SGB y otras variantes, Región Metropolitana de Recife, 2015

Variables n (%)

UCI 6 (13)

Ventilación mecánica 12 (26)

Sonda vesical permanente 10 (22)

Sonda nasoenteral 11 (24)

Mediana (Mín – Máx)

Tiempo de internación 13 días (1 – 81 días)

Tiempo en la UCI 4 días (1 – 21 días)

Tiempo en ventilación mecánica 7 días (1 – 41 días)

N=46

Distribución de los casos de SGB y variantes según la evolución, región metropolitana de Recife, 2015

Variables n (%)

Evolución

Cura con secuelas 19 (54)

Cura 20 (30)

Decesos 7 (16)

N=46

Muestra del Ministerio de Salud de Brasil – EPISUS Alteraciones neurológicas - Pernambuco

¿HAY MUCHO POR ELUCIDAR?

Ene Feb Mar Abr May Jun Jul Ago Set Oct Nov Dic

73

164

303

182


Ep

ide

mia

de

Zik

a

Epid

em

ia d

e Z

ika

Zik

a

Epid

em

ia d

e

Zik

a

Estándar de brote de casos neurológicos

1 El tiempo entre la manifestación clínica del Zika y el aparecimiento de los cuadros neurológicos

es más corto que el esperado en muchos casos

Hipótesis: puede haber un efecto citopático directo producido por el vírus, más allá del

inmunomediado (Dos picos de casos)

2 Hipótesis: ¿Los casos neurológicos y el SGB son más graves en el Zika?

El estudio de caso, el control, podrá ofrecer una respuesta.

Ep

ide

mia

de

Zik

a

Neu

ro

Neu

ro

Neu

ro

Ene Feb

Neu

ro

Ep

idem

ia d

e Z

ika

Ep

idem

ia d

e Z

ika

Neu

ro

Neu

ro

Ep

ide

mia

de

Zik

a

Neu

ro

Puntos relevantes:

41 casos serología Zika IgM

Controles de la población general (n: 98): 17% IgM positivo

PCR todos negativos para los casos de SGB

Progresión rápida para el cuadro neurológico posterior al Zika

(6 días)

MICROCEFALIA – VISIÓN DE LA ASISTENCIA

19/10/15

19/10/15

Neurólogo= relato

de aumento

microcefalia.

Se solicita la

opinión del clínico

por su experiencia

en brotes

20/11/15. Visita al IMIP

Dra. Jucile Menezes.

16 niños internados

con microcefalia


nunca vieron un

número tan elevado de

casos en tan poco

tiempo" = esto de por

sí supone una

investigación.

Se efectuaron

entrevistas con las

madres, se tomaron

muestras de suero

(madres-niños) y LCR.

La historia clínica

epidemiológica = Zika

Se formula hipótesis

20/10/15

CONSIDERACIONES - ARBOVIROSIS

Sugerimos la arbovirosis, como uno de los posibles agentes que deben ser

investigados y como principal hipótesis, baseados en los seguintes

argumentos:

Aparecimiento de muchos casos, en poco tiempo, simultáneamente en

diferentes ciudades y estados, se caracteriza por ser una enfermedad con

altas tasas de ataques y rápida diseminación, fenómeno asociado a

enfermedades transmitidas por artrópode.

Enfermedades asociadas a TORCH, incluyendo CMV, por las vías de

transmisión, no está asociado a grandes brotes, ni ocurren

simultáneamente en diferentes ciudades.

La investigación durante el prenatal y el perinatal arrojaron resultados

negativos para TORCH en los primeiros casos.

Por el tipo de malformación, la exposición debe haber ocurrido en el primer

trimestre del embarazo.

Carlos Brito UFPE

CONSIDERACIONES - ARBOVIROSIS

La mayoría de las madres (63%) relatava haber tenido un cuadro viral compatible con

enfermedad exantemática en el primer trimestre de 2015.

Tuvimos en Pernambuco, en el primer semestre, un gran brote de virus Zika.

El Zika tiene un neurotropismo mayor que en otras arbovirosis. (Demostrado en modelo

animal y sospechoso en la Polinesia Francesa) y confirmado en Pernambuco.

El Ministerio de Salud de Brasil investiga en este momento casos neurológicos en adultos

y niños, asociados al ZikV, en otros estados.

Otras arbovirosis como el Dengue, endémica y epidémica en la región, no están

asociadas a malformaciones congénitas (7), en la chikungunya, pese a estar relacionada

a enfermedad perinatal, no hay evidencias de malformaciones (8), bien así como el ChikV

aun no había sido detectado en estos dos estados a principios de año.

Carlos Brito UFPE/Fiocruz-PE

Variable

Edad (años) Mediana (Intervalo)

23 (15 - 38)

Síntomas n (%)

Exantema 24 (63,2)

Tipo Difuso 18 (75)

Fiebre 11 (45,8)

Artralgia 08 (33,3)

Edema 02 (8,3)

Conjuntivitis 0 (0)

Resultados preliminares - Caso Microcefalia N=38

Carlos Brito UFPE

Variable

Exantema Mediana (Intervalo)

Periodo de embarazo 3 (1 - 4)

Resultados preliminares - Caso Microcefalia N=24

1

6

14

1

0

2

4

6

8

10

12

14

16

1 mês 2 mês 3 mês 4 mês

M E S D E G E STAC IÓ N D E L

R E L ATO D E E X A NT EMA

58%

21%

Carlos Brito UFPE

MALFORMACIONES DEL SN – ESTACIONALIDAD

PERNAMBUCO

Jan Fev Marc Abril Maio Junh Julho Agost Set Out Nov Dez

2011 9 6 13 11 3 6 7 5 9 12 3 2

2012 4 8 13 7 6 6 5 14 9 3 6

2013 3 8 7 7 10 5 8 15 4 6 4 6

0

2

4

6

8

10

12

14

16

N c

aso

s

Todas Malformaciones Congénitas/

año/mes-PE

2011 2012 2013

Malformações SNC 86 88 83

80

82

84

86

88

Tít

ulo

de

l E

je

Malformaciones Congénitas

del Sistema Nervioso/año-PE

2011 2012 2013 2014 2015

N casos Microcefalia 5 9 10 12 58

0

10

20

30

40

50

60

70

N c

aso

s

N casos Microcefalia

Carlos Brito UFPE

INVESTIGACIÓN– AMPLIA

Epidemias ocasionadas por la introducción de nuevos

teratógenos en la historia:

misoprostol (Cytotec) (Castilla y Orioli, 1994; Orioli y Castilla,

2000),

talidomida (Castilla et al., 1996; Schuler-Faccini et al., 2007),

contaminantes ambientales con ac ción geográficamente

localizada, por ejemplo:

• Cubatão (SP) en 1978 (Monteleone-Neto y Castilla, 1994),

• Goiânia (GO) (Nenot, 1990) en 1987 y

• Caçapava (SP) (Dutra, 1996) en 1988.

Carlos Brito UFPE

AGENTES INFECCIOSOS

Complejo TORCH

• T- Toxoplasmosis

• O- Otras infecciones (Coxsackie, Sífilis, VZV, VIH, Parvovirus

B19, HBV, LCM)

• R- Rubeola

• C- Citomegalovirus

• H – Herpes simplex 1 y 2

Arbovirosis: Dengue, Chikungunya, Zika, Oropouche, Nilo

Occidental, St. Louis, Rocio, etc.

Nuevas Vacunas de virus introducidas en el país (?)

Carlos Brito UFPE

¿PUEDE SER DENGUE?

Se cuenta con suficientes evidencias de que la enfermedad no causa

malformaciones.

Un cambio de comportamiento (mutación) es poco probable.

Carlos Brito UFPE

¿PUEDE SER CHIKUNGUNYA? Algunas buenas evidencias (suficientes) de que la enfermedad no causa

malformaciones

No tuvimos casos o brotes de chikungunya durante el primer trimestre en

Pernambuco

N: 590 embarazadas infectadas por ChikV

Nuestro estudio no encontró ninguna

evidencia de enfermedad congénita en

recién nacidos vivos asintomáticos

expuestos al CHIKV durante el embarazo

RESEARCH

and the mean acceptance rate was 70% (49/70); 43% (21)

of the women included thought that they had had chikun-

gunya infection during pregnancy compared with 6% (4) of

those not included (p<0.0001). Mean parity (2.1 vs. 2.6; p

= 0.08), mean maternal age (28.6 years vs. 29.1 years; p =

0.70), mean gestational age at delivery (39.1 weeks vs. 38.7

weeks; p = 0.14), and mode of delivery (18% vaginal vs.

17% cesarean; p = 0.87) did not differ between the women

who were or were not included.

Discussion

In this comparative study, we did not observe any ef-

fect of chikungynya infection on pregnancy outcomes ex-

cept for the number of prenatal maternal hospital admis-

sions for chikungunya symptoms. Our study involved a

high proportion of maternity units and births in Réunion.

Women included in the study in April 2006 accounted for

73% (905/1,240) of all live births in Réunion. Systematic

determination of serologic status by identifi cation of spe-

cifi c IgM and IgG confi rmed infection status. All patients

for whom chikungunya infection during pregnancy was un-

certain were excluded. We excluded women who had posi-

tive serologic results but did not report symptoms or have

a positive RT-PCR result because we could not identify the

date of infection. Studies during the outbreak in Réunion

showed that IgM tended to persist for 12 to 24 months and

cannot be used to identify the date of infection (21).

Because inclusion in the study began in April 2006 after

the outbreak had peaked, we could not analyze pregnancies

completed before this date. Therefore, our study does not

describe the consequences of the outbreak on the risk for

miscarriage or preterm delivery during the fi rst quarter of

2006. The study included only pregnancies with outcomes

after that quarter. Most of the women were infected before

422 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 16, No. 3, March 2010

Table 3. Pregnancy outcome according to chikungunya virus infection during pregnancy, Réunion, France, 2006*

CharacteristicInfected,†

no. (%), n = 658 Not infected,‡

no. (%), n = 655 p value Unadjusted OR

(95% CI) Adjusted OR

(95% CI)

Hospital admission during pregnancy

Yes 266 (40.4) 191 (29.2) 1.65 (1.31–2.07) 1.52 (1.18–1.95)

No 392 (59.6) 464 (70.8) <0.0001 1 1

Hospital admission during pregnancy, suspected infection with chikungunya virus excluded

Yes 180 (28.0) 136 (26.1) 0.91 (0.70–1.18) 0.83 (0.62–1.10)

No 464 (72.0) 385 (73.9) 0.48 1 1

Vaginal bleeding during pregnancy

Yes 55 (8.4) 68 (10.4) 0.79 (0.55–1.15) 0.94 (0.63–1.42)

No 596 (91.6) 584 (89.6) 0.22 1 1

Obstetric hemorrhaging

Yes 36 (5.6) 42 (6.5) 0.85 (0.54–1.35) 0.87 (0.53–1.42)

No 609 (94.4) 605 (93.5) 0.49 1 1

Mode of delivery§

Vaginal 545 (83.8) 530 (81.5) 0.27 1 1

Cesarean 105 (16.2) 120 (18.5) 0.85 (0.64–1.14) 0.77 (0.56–1.06)

Mean gestational age, wk§ 39.0 (2.1) 38.9 (2.5) 0.55

<32 8 (1.2) 15 (2.3) 0.26 0.52 (0.22-1.24) 0.48 (0.19–1.23)

32–36 53 (8.2) 60 (9.2) 0.86 (0.59–1.27) 0.78 (0.51–1.20)

>37 589 (90.6) 575 (88.5) 1 1

Mean birthweight, g§ 3,116 (549) 3.056 (620) 0.27

<2,000 20 (3.1) 32 (4.9) 0.36 0.62 (0.35–1.11) 0.66 (0.36–1.22)

2,000–2,999 235 (35.9) 236 (35.7) 0.99 (0.79–1.25) 1.01 (0.79–1.30)

3,000–3,999 372 (56.9) 371 (56.1) 1 1

>4,000 27 (4.1) 22 (3.3) 1.22 (0.69–2.19) 1.25 (0.65–2.39)

Stillbirth after 22 wk§

Yes 5 (0.8) 8 (1.2) 0.63 (0.20–1.93) 0.61 (0.18–2.07)

No 653 (99.2) 656 (98.8) 0.41 1 1

Congenital malformation

Yes 19 (2.9) 15 (2.2) 1.36 (0.68–2.74) 1.54 (0.68–3.49)

No 647 (97.1) 654 (97.8) 0.48 1 1

Admission to neonatal care§

Yes 53 (8.1) 55 (8.3) 0.97 (0.65–1.44) 1.03 (0.67–1.58)

No 605 (91.9) 609 (91.7) 0.88 1 1

*OR, odds ratio; CI, confidence interval. OR was adjusted for center, educational level, body mass index, and maternal age. Women infected before pregnancy were considered not infected during pregnancy. †Of the 658 women who were infected, 650 had delivered a child after 22 weeks; 658 children were delivered by these women. ‡Of the 655 women who were not infected, 650 had delivered a child after 22 weeks; 664 children were delivered by these women. §Miscarriage before 22 weeks was excluded.

RESEARCH

and the mean acceptance rate was 70% (49/70); 43% (21)

of the women included thought that they had had chikun-

gunya infection during pregnancy compared with 6% (4) of

those not included (p<0.0001). Mean parity (2.1 vs. 2.6; p

= 0.08), mean maternal age (28.6 years vs. 29.1 years; p =

0.70), mean gestational age at delivery (39.1 weeks vs. 38.7

weeks; p = 0.14), and mode of delivery (18% vaginal vs.

17% cesarean; p = 0.87) did not differ between the women

who were or were not included.

Discussion

In this comparative study, we did not observe any ef-

fect of chikungynya infection on pregnancy outcomes ex-

cept for the number of prenatal maternal hospital admis-

sions for chikungunya symptoms. Our study involved a

high proportion of maternity units and births in Réunion.

Women included in the study in April 2006 accounted for

73% (905/1,240) of all live births in Réunion. Systematic

determination of serologic status by identifi cation of spe-

cifi c IgM and IgG confi rmed infection status. All patients

for whom chikungunya infection during pregnancy was un-

certain were excluded. We excluded women who had posi-

tive serologic results but did not report symptoms or have

a positive RT-PCR result because we could not identify the

date of infection. Studies during the outbreak in Réunion

showed that IgM tended to persist for 12 to 24 months and

cannot be used to identify the date of infection (21).

Because inclusion in the study began in April 2006 after

the outbreak had peaked, we could not analyze pregnancies

completed before this date. Therefore, our study does not

describe the consequences of the outbreak on the risk for

miscarriage or preterm delivery during the fi rst quarter of

2006. The study included only pregnancies with outcomes

after that quarter. Most of the women were infected before


Table 3. Pregnancy outcome according to chikungunya virus infection during pregnancy, Réunion, France, 2006*

CharacteristicInfected,†

no. (%), n = 658 Not infected,‡

no. (%), n = 655 p value Unadjusted OR

(95% CI) Adjusted OR

(95% CI)

Hospital admission during pregnancy

Yes 266 (40.4) 191 (29.2) 1.65 (1.31–2.07) 1.52 (1.18–1.95)

No 392 (59.6) 464 (70.8) <0.0001 1 1

Hospital admission during pregnancy, suspected infection with chikungunya virus excluded

Yes 180 (28.0) 136 (26.1) 0.91 (0.70–1.18) 0.83 (0.62–1.10)

No 464 (72.0) 385 (73.9) 0.48 1 1

Vaginal bleeding during pregnancy

Yes 55 (8.4) 68 (10.4) 0.79 (0.55–1.15) 0.94 (0.63–1.42)

No 596 (91.6) 584 (89.6) 0.22 1 1

Obstetric hemorrhaging

Yes 36 (5.6) 42 (6.5) 0.85 (0.54–1.35) 0.87 (0.53–1.42)

No 609 (94.4) 605 (93.5) 0.49 1 1

Mode of delivery§

Vaginal 545 (83.8) 530 (81.5) 0.27 1 1

Cesarean 105 (16.2) 120 (18.5) 0.85 (0.64–1.14) 0.77 (0.56–1.06)

Mean gestational age, wk§ 39.0 (2.1) 38.9 (2.5) 0.55

<32 8 (1.2) 15 (2.3) 0.26 0.52 (0.22-1.24) 0.48 (0.19–1.23)

32–36 53 (8.2) 60 (9.2) 0.86 (0.59–1.27) 0.78 (0.51–1.20)

>37 589 (90.6) 575 (88.5) 1 1

Mean birthweight, g§ 3,116 (549) 3.056 (620) 0.27

<2,000 20 (3.1) 32 (4.9) 0.36 0.62 (0.35–1.11) 0.66 (0.36–1.22)

2,000–2,999 235 (35.9) 236 (35.7) 0.99 (0.79–1.25) 1.01 (0.79–1.30)

3,000–3,999 372 (56.9) 371 (56.1) 1 1

>4,000 27 (4.1) 22 (3.3) 1.22 (0.69–2.19) 1.25 (0.65–2.39)

Stillbirth after 22 wk§

Yes 5 (0.8) 8 (1.2) 0.63 (0.20–1.93) 0.61 (0.18–2.07)

No 653 (99.2) 656 (98.8) 0.41 1 1

Congenital malformation

Yes 19 (2.9) 15 (2.2) 1.36 (0.68–2.74) 1.54 (0.68–3.49)

No 647 (97.1) 654 (97.8) 0.48 1 1

Admission to neonatal care§

Yes 53 (8.1) 55 (8.3) 0.97 (0.65–1.44) 1.03 (0.67–1.58)

No 605 (91.9) 609 (91.7) 0.88 1 1

*OR, odds ratio; CI, confidence interval. OR was adjusted for center, educational level, body mass index, and maternal age. Women infected before pregnancy were considered not infected during pregnancy. †Of the 658 women who were infected, 650 had delivered a child after 22 weeks; 658 children were delivered by these women. ‡Of the 655 women who were not infected, 650 had delivered a child after 22 weeks; 664 children were delivered by these women. §Miscarriage before 22 weeks was excluded.

Mother-to-child transmission of chikungunya virus was

reported during the 2005–2006 outbreak on Réunion Island,

France. To determine the effects of this virus on pregnancy

outcomes, we conducted a study of pregnant women in

Réunion in 2006. The study population was composed of

1,400 pregnant women (628 uninfected, 658 infected during

pregnancy, 27 infected before pregnancy, and 87 infected

on unknown dates). We compared pregnancy outcomes for

655 (628 + 27) women not infected during pregnancy with

658 who were infected during pregnancy. Infection occurred

during the fi rst trimester for 15% of the infected women, the

second for 59%, and the third for 26%. Only hospital admis-

sion during pregnancy differed between infected and unin-

fected women (40% vs. 29%). Other outcomes (cesarean

deliveries, obstetric hemorrhaging, preterm births, stillbirths

after 22 weeks, birthweight, congenital malformations, and

newborn admissions) were similar. This virus had no ob-

servable effect on pregnancy outcomes.

Chikungunya virus infection is transmitted by mosqui-

toes of the genus Aedes. The virus was fi rst isolated in

1952 and is found in eastern Africa, India, and Southeast

Asia. Symptoms of infection are high fever and disabling

muscle and joint pain, often associated with a rash and

mild bleeding. Persons infected usually recover spontane-

ously in several days to a week (1). Fever and arthralgia

may occur for several months or even years (2). Patients are

treated only for their symptoms because there is no specifi c

treatment for the underlying infection (3). Before the recent

outbreak on the island of Réunion, the disease was not con-

sidered life-threatening.

Réunion, a French territory in the southwestern Indian

Ocean, has a population of ≈785,000 inhabitants. Medical

facilities in Réunion are similar to those in mainland France

and other industrialized countries. A major chikungunya

outbreak occurred in Réunion in 2005–2006. At the end of

this outbreak, seroprevalence was estimated to be 38.2%

(95% confi dence interval [CI] 35.9%–40.6%); 300,000

(95% CI 283,000–320,000) persons were infected (4,5).

Aedes albopictus mosquitoes were the primary vector in

this outbreak.

The outbreak began in eastern Africa (6). It reached

Réunion in March 2005 but was relatively inactive, with

only several thousand cases until November 2005, when

its incidence unexpectedly increased during summer in the

Southern Hemisphere, peaking at 47,000 cases/week dur-

ing week 5 of 2006. The most recent cases were reported

in August 2006. Comparisons of 2006 with previous years

showed that mortality rates increased during February,

March, and April 2006 (7,8). Since 2006, the virus has

caused several epidemics in the Indian Ocean region (Mad-

agascar, India, Sri Lanka, Thailand, Malaysia, and Singa-

pore). Three new cases of chikungunya were reported in

August 2009 on Réunion Island (9).

The fi rst cases of virus transmission from mother to

child at birth were identifi ed in February 2006; a total of 38

such cases were reported (10,11). The virus was also found

Chikungunya Virus Infection during

Pregnancy, Réunion, France, 2006

Xavier Fritel, Olivier Rollot, Patrick Gérardin, Bernard-Alex Gaüzère, Jacques Bideault,

Louis Lagarde, Barbara Dhuime, Eric Orvain, Fabrice Cuillier , Duksha Ramful, Sylvain Sampériz,

Marie-Christine Jaffar-Bandjee, Alain Michault, Liliane Cotte, Monique Kaminski,

Alain Fourmaintraux, and the Chikungunya-Mère-Enfant Team

RESEARCH


Author affi liations: Centre Hospitalier Régional de la Réunion, Saint-

Denis, France (X. Fritel, P. Gérardin, B.-A. Gaüzère, E. Orvain, F.

Cuillier, D. Ramful, S. Sampériz, M.-C. Jaffar-Bandjee, A. Michault,

L. Cotte, A. Fourmaintraux); Centre d’Investigation Clinique–Epi-

démiologie Clinique de la Réunion, Saint-Denis (O. Rollot, P. Gé-

rardin); Institut National de la Santé et de la Recherche Médicale,

Villejuif, France (X. Fritel, P. Gérardin, M. Kaminski); Centre Hos-

pitalier Intercommunal de Saint-Benoit-Saint-André, Saint-Benoit,

France (J. Bideault); Centre Hospitalier Gabriel-Martin, Saint-Paul,

France (L. Lagarde); Clinique Sainte-Clotilde, Saint-Denis (B. Dhu-

ime); and Université Pierre et Marie Curie 6, Paris, France (X. Fri-

tel, P. Gérardin, M. Kaminski)

DOI: 10.3201/eid1603.091403

Chikungunya Virus during Pregnancy

in specimens from 3 early second trimester miscarriages

(12). When this outbreak began, little information was

available about the risk for chikungunya virus infection in

pregnant women. In addition to virus transmission at birth,

potential complications include transplacental transmission

before birth, congenital malformations, stillbirths, growth

restriction, and preterm delivery. Chikungunya virus be-

longs to the same family of viruses (Togaviridae) as rubella

virus, for which some of these complications have been de-

scribed (13). The high fever that characterizes chikungu-

nya infection could cause uterine contractions or fetal heart

rate abnormalities, which might promote spontaneous or

induced preterm delivery (cesarean for fetal salvage). The

hemorrhagic syndrome described at the onset of infection

might be manifested by vaginal bleeding during pregnancy

or third-stage hemorrhaging, as reported for infection with

dengue virus (14,15). The proportion of symptomatic and

asymptomatic infections was also unknown.

The purpose of our study (the Chikungunya-Mère-

Enfant cohort study) was to determine the consequences of

chikungunya infection on pregnancy outcomes. These re-

sults will be useful to public health offi cials and physicians

who provide care for pregnant women or newborns because

chikungunya can be imported by international travelers and

the location of Ae. albopictus mosquitoes has extended be-

yond the tropics (16). These mosquitoes are found in 26

states in the United States and several countries in Europe,

where outbreaks are possible (17,18).

Methods

We began our study in early April 2006, by planning

to recruit all pregnant women (with or without symptoms

of chikungunya infection) who received care at 1 of the 6

main maternity units in Réunion. These 6 units accounted

for 78% of 14,077 live births in Réunion in 2006. Inclusion

in the study was proposed regardless of the reason for a vis-

it or admission. We had planned to include 3,600 women so

that suffi cient children with in utero chikungunya infection

were available to study their psychomotor development. To

show a difference of 10 points in the developmental quo-

tient at 24 months of age, it would have been necessary to

observe 19 children infected in utero. However, because of

the decrease in the outbreak after June 1, we revised our

sample size and included only pregnant women who re-

ported clinical signs suggestive of this infection. The study

cohort was composed of 1,400 pregnant women (mean

term 32 weeks); 1,384 (99%) gave birth in 1 of the 6 partic-

ipating maternity units. Information on pregnancy outcome

for 16 women lost to follow-up was obtained by contacting

each one directly. A total of 914 participants were included

in April, 386 in May, 88 in June, 5 in July, 2 in August, 4 in

September, and 1 in November. In an ancillary study, for 3

days in May 2006, all women who gave birth in the 6 par-

ticipating units were interviewed to determine how women

in the study cohort differed from those not in the study in

terms of chikungunya symptoms, parity, age, gestational

age of the infant at birth, and mode of delivery.

Serologic status for chikungunya virus infection was

determined at participant’s inclusion in the study. All re-

ports of chikungunya fever were confi rmed by using se-

rologic testing or detection of the viral genome in any

specimen by using real-time reverse transcription–PCR

(RT-PCR) (19,20). Serologic tests with negative results

at inclusion were repeated at delivery or when symptoms

suggestive of infection appeared. Histologic examinations

were performed on placentas of all women who had chi-

kungunya infection during pregnancy. RT-PCR was also

performed for placenta and amniotic fl uid samples from

women with symptoms at delivery.

Date of infection was determined by checking patient

history of symptoms or by RT-PCR when available. Wom-

en were classifi ed into 2 groups: those infected by chikun-

gunya virus during pregnancy (symptoms during pregnan-

cy confi rmed by positive serologic or RT-PCR results) and

those not infected (negative serologic results at delivery

or during the preceding 7 days). Women infected before

pregnancy were considered not infected during pregnancy.

We excluded women who were infected but asymptomatic,

those whose symptoms could not be dated, and those with

inconclusive serologic results from analysis.

We analyzed how women infected by chikungunya vi-

rus during pregnancy (658) differed from those who were

not infected (655) for general characteristics (age, educa-

tional level, marital status, and body mass index), medical

history (diabetes and hypertension), and obstetric history

(previous pregnancies, history of preterm delivery, small-

for-gestational-age, or stillbirths). We then compared

pregnancy outcomes (prenatal hospital admission for any

reason and for chikungunya symptoms, vaginal bleeding

during pregnancy, mode of delivery, obstetric hemorrhage,

stillbirth, preterm birth, birthweight, congenital malforma-

tions, and newborn hospitalization) between the 2 groups.

Obstetric hemorrhage was defi ned as blood loss >500 mL.

We considered only fetal malformations recognized by Eu-

ropean Surveillance of Congenital Abnormalities (EURO-

CAT) (www.eurocat.ulster.antibodies.uk). All malforma-

tions recorded were verifi ed by checking either pediatric

fi les or the Réunion congenital anomalies registry, which is

affi liated with EUROCAT.

Bivariate analysis of pregnancy outcomes compared

means (by Wilcoxon rank-sum test) and percentages (χ2 or

Fisher exact tests). For multivariate analysis, we adjusted

for center, maternal age, educational level, and body mass

index. Logistic regression was used to estimate the ad-

justed odds ratios (ORs). A p value <0.05 was considered

signifi cant. Sensitivity analyses were performed to deter-

Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 16, No. 3, March 2010 419

Comparamos los resultados del embarazo para 655 (628 + 27), las

mujeres no infectadas durante el embarazo con 658 que fueron

infectadas durante el embarazo.

Conclusión: No hubo diferencia en los desenlaces (partos cesáreos,

hemorragia obstétrica, nacimientos prematuros, natimuertos después de

22 semanas, peso al nacer, malformaciones congénitas, y de admisión

de recién nacidos). No se observaron efectos de este virus en los

resultados del embarazo.

MICROCEFALIA – VISIÓN DE LA ASISTENCIA

19/10/15

19/10/15

Adélia Henriques

(Neuróloga)= relato

de aumento

microcefalia/

enfermedad viral

antecedente.

Se solicita la

opinión del clínico

debido a su

experiencia en

brotes

26/10/15

26/10/15.

Reunión de técnicos

en un consejo

técnico del

CREMEPE –

Multidisciplinar –

debatir protocolos e

impresiones.

Se propone una

amplia investigación.

Zika fuerte candidato

(datos clínico-

epidemiológicos)

11/11/15

11/11/15.

Gobierno

Federal

declara

estado de

emergencia

en la Salud

Publica

22/10/15.

Comunicado al

PNCD

(Claudio

Maierovitch

Giovanine Evelin)

26 casos en 3

maternidades con

caracterización

suficiente para

una notificación

oficial a la OMS

Se elabora

comunicado en

conjunto

asistencia y SSE-

PE, MS.

22/10/15

20/11/15. Visita al IMIP

Dra. Jucile Menezes.

16 niños internados

con microcefalia


nunca vieron un

número tan elevado de

casos en tan poco

tiempo" = esto de por

sí supone una

investigación.

Se entrevista a las

madres, se toman

muestras de suero

(madres-niños) y LCR.

Historia clínica de la

infección previa = Zika

Se formula hipotesis

20/10/15

21/10/15

Dra. Kleber Luz-RN

Efectua una búsqueda

activa en la asistencia y

confirma el aumento de

casos con antecedente

compatíble con Zika.

Toma fuerza la hipótesis

de arbovirosis

21/10/15

17/11/15.

Liq Amniótico en

gestantes con

microcefalia en PB

PCR+ para Zika

“Es altamente

probable que el

aumento de casos

esté relacionado con

el Zika”

Claudio Maierovitch

17/11/15

CUESTIONES PERTINENTES

¿POR QUÉ NO SE DETECTARON CASOS DE MICROCEFALIA EN LA POLINESIA FRANCESA?

Hipótesis: enfermedad con tasas de incidencia pequeñas, se necesita un "gran

volumen" para ser percibida.

Referencial: Incidencia estimada de microcefalia por 1.000 NV en Pernambuco, últimos 4 años: 0,05 (2011 a

2014)

Polinesia Francesa

o Población 270.000

o Tasa de natalidad por 1000 hab: 15

o En 2014: alrededor de 4.000 nacidos vivos

o Incidencia estimada de microcefalia 0,05/1000: serían 0.2 casos/año - 01 caso por año

o Si ocurriera un aumento del 500% en la Polinesia, serían 4 casos en un año.

Conclusión: es difícil que la asistencia perciba puntos fuera de la curva, en poblaciones pequeñas y en pequeños

números de nacidos vivos, aunque todos ocurrieran el mismo mes.

Pernambuco:

o 144.000 nacidos vivos por año

o Microcefalia estimada (media): 7 casos por año (osciló de 5 a 12 casos en los últimos 4 años).

o En 2015, en cuanto fue percibida por la asistencia, fueron 28 casos en un único mes

o Otros 20 casos ya habían sido notificados al SINASC, y el sistema no había notado este incremento, pero ya

representaba 100% de aumento: nótese la dificultad para identificar el punto fuera de la curva

o El aumento en escala (28 casos) llevó a la captación a través de la asistencia

Conclusión: las exposiciones con pequeñas tasas de incidencia, que conducen a desenlaces como estos, apenas son

perceptibles en grandes poblaciones, con altas tasas de natalidad

¿ASOCIACIÓN Y PERSPECTIVA?

Ene Feb Mar Abr May Jun Jul Ago Sep Oct Nov Dic M

icro

ce

falia

Mic

roce

falia

73

164

303

182


Ep

ide

mia

de

Zik

a

Epid

em

ia d

e Z

ika

Zik

a

Epid

em

ia d

e

Zik

a

¿Cuándo quedaron embarazadas?

1 Hipótesis: estamos viendo gestantes expuestas en enero/febrero que tuvieron sus bebés en

septiembre/octubre.

Conclusión: Estaríamos entonces en el inicio de la epidemia, ya que en marzo fue el mayor pico y

exposición.

Error: el análisis detectó que estas madres fueron expuestas exactamente en el 3º mes de

embarazo, en consecuencia, estaríamos viendo madres expuestas en el mes de pico de la

epidemia.

2 Hipótesis: madres que estaban en el primer o segundo mes de embarazo en el pico de la

epidemia (marzo), en noviembre y diciembre, fecha prevista para el parto, aparecerán casos en

igual proporción.

¿Estos niños presentarán malformaciones más graves?

3 Hipótesis: una infección congénita asociada a una malformación está relacionada a mayor frecuencia de aborto.

¿Tuvimos un aumento del número de abortos en el primer semestre de este año?

Mic

roce

falia

Mic

roce

falia

Ep

ide

mia

de

Zik

a

Mic

roce

falia

Mic

roce

fal

ia

Ene Feb

Neu

ro

Neu

ro

Neu

ro

Neu

ro

Neu

ro

Neu

ro

NÚMERO DE CASOS POR 10.000 NACIDOS VIVOS

(BASE POBLACIONAL-BRASIL) REPORTE 2015 - 15/02/2016

Pernambuco

* N casos

Microcefalia

Nacidos

vivos

2014

N casos/

nacidos vivos

10000

600 153.252 39,15

Rio Grande

do Norte

N casos

Microcefalia

Nacidos

vivos 2014

N casos/

nacidos vivos

10000

298 50.608 58,88

Paraíba

N casos

Microcefalia

Nacido vivos

2014

N casos/

nacidos vivos

10000

479 61.464 77,93

Sergipe

N casos

Microcefalia

Nacidos

vivos 2014

N casos/

nacidos vivos

10000

185 37.106 49,86

Bahia

N casos

Microcefalia

Nacidos

vivos 2014

N casos/

nacidos vivos

10000

316 220.444 14,33

Ceará N

casos

Microcefalia

Nacidos

vivos 2014

N casos/

nacidos vivos

10000

266 134.906 19,72

Pernambu

coParaíba Sergipe RN Alagoas Piauí Ceará Bahia Maranhão

casos/10.000 nv 39,15 77,93 49,86 58,88 20,23 20,72 19,72 14,33 12,78

0,00

10,00

20,00

30,00

40,00

50,00

60,00

70,00

80,00

90,00

Tít

ulo

de

l E

je

casos/10.000 nv

INFECCIÓN CONGÉNITA ASOCIADA AL ZIKA

O EL ZIKA CONGÉNITO

el virus zika en brasil: relato de una epidemia · edema mmss e mmii 51 52,9 116 69,5 0 0 167 n...

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