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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/