Zika Virus a new member of the TORCH family?

Transcription

1 Zika Virus a new member of the TORCH family?

2 Zika Virus ~Carries the name of the forest where it was first identified, a name that means overgrown in the Luganda language ~was first isolated in 1947 from the serum of a sentinel rhesus monkey from the Zika forest ~ An RVA virus that belongs to the Flaviviridae family, and Flavivirus genus, whose members are composed of a protein capsid covered by a lipid envelope in which the membrane protein and glycoprotein spikes are inserted

3 Uganda where it all began

4 Uganda where it all began

5 Zika itinerary Virus detected in Thailand, Malaysia, Uganda, Nigeria, Indonesia, Senegal and Cote d Ivoire First occurrence of human infection evidenced by the presence of neutralizing antibodies in the sera of east African residents In Nigeria In other studies antibodies were detected in HEALTHY people from India, Egypt, Vietnam, Kenya, Sierra Leone and Pakistan

6 zika travel itinerary

7 Zika travels to Yap Islands Over 70% of Yap residents were affected No deaths or hospitalizations were associated with Zika during this outbreak

8 Zika travels to Micronesia In 2007, an outbreak of illness characterized by rash, conjunctivitis, fever, arthralgia and arthritis was reported on Yap Island, Micronesia This was the first outbreak of ZIKV disease outside Africa and Asia It is estimated that over 70% of Yap residents were infected

9 Zika virus itinerary In 2013, approximately 10% of the population, (about 29,000 people),sought medical care due to a Zika virus outbreak in French Polynesia. This was the first time that ZIKV was associated with severe disease. Although no deaths were reported, 72 cases were classified as severe and included neurological or autoimmune presentations. The outbreak spread to other islands in Oceania New Caledonia, The Cook Islands, Vanuatu, and the Solomon Islands. French Polynesian authorities reported a significant increase in cases of CNS abnormalities in fetuses born between 2014 and 2015, which was the period following the ZIKV outbreak in that region

10 Transmission ~During the outbreak in French Polynesia, a study to investigate ZIKV in blood donors was carried out. ~It was noted that 3% of donors were asymptomatic hosts of the virus, but no case of infection was identified after blood transfusion in that country. Later. results suggest that testing for ZIKV must be implemented in the routine of blood donation. ~Another French Polynesian study found cases in which RT PCR was positive in mother s milk and baby s and mother s saliva, so that these possible sources of infection should be considered.

11 Transmission of Zika Virus ZIKV is mainly transmitted by the Aedes aegypti vector, which resides in tropical and subtropical regions, as well as by the Aedes albopictus, an inhabitant of the European Mediterranean region. After the mosquito s bite, there is an incubation period of about nine days, and then symptoms ensue. Although there is no evidence of sexual transmission by other arboviruses,(like Dengue), some authors hypothesized that this could be possible for ZIKV. Patients exposed to endemic areas showed usual symptoms of the disease and one atypical sign of hematospermia. In such cases the presence of virus in semen was confirmed by serological tests or by RT PCR. In addition, sexual partners of these patients had similar symptoms, strengthening this assumption that sexual transmission was possible.

12 Zika travel itinerary next stop Easter Island in 2014, then on to Brazil in 2015 ~The first indigenous transmission within an American territory ~ Phylogenic analysis revealed that the first outbreak of ZIKV in the Americas occurred on Easter Island (a Chilean island located in the South Pacific).The virus was most closely related to those cases from French Polynesia. ~In 2015 the Brazilian Ministry of Health confirmed the autochthonous transmission of ZIKV in their country the first cases of an exanthematic illness associated with fever, conjunctivitis and arthralgia were reported in the northeast region of Brazil.

13 Zika spreads to the Americas

14 A worldwide Zika Epidemic On February 1, 2016, the World Health Organization, (WHO), declared a global public health emergency due to the ZIKA threat. Any remaining doubts about the relationship between Zika virus and the consequences of intrauterine infection were eliminated by April 13,2016, when investigators from the Center for Disease Control, (CDC),reported that sufficient evidence had accumulated to offer a causal association between prenatal ZIKV infection and microcephaly and other fetal malformations.

15 Zika and fetal Malformations By February 2016,there were 22 Brazilian states that had confirmed ZIKV transmission associated with fetal malformations and death. Brazilian health authorities reviewed reports of more than 5600 suspected cases of microcephaly in newborns, ( an increase of more than 20 times the historical average over the past 5 years). There were 120 deaths due to congenital malformations believed to be related to ZIKV.

16 Zika and microcephaly

17 Zika in Brazil

18 Zika virus Microcephaly

19 Birth defects potentially related to Zika virus infection Congenital microcephaly Intracranial calcifications Cerebral atrophy Abnormal cortical formation: (polymicrogyria,lissencephaly schizencephaly, pachygyria) Corpus callosum abnormalities Cerebellar abnormalities Porencephaly Hydranencephaly Ventriculomegaly Fetal brain disruption sequence (collapsed skull, overlapping sutures, prominent occipital bone, scalp ruggae) o

20 Zika brain calcifications

21 Zika virus syndrome abnormalities A= micropthalmia B=reducedcerebral volume and subcortical calcifications C=ventriculomegaly, abnormal cortical development(lissenceph) D=brainstem hypoplasia E=cerebellar hypoplasia F=reduced cerebral volume G=abnormal cortical development H= cerebellar hypoplasia I= subcortical calcifications

22 Fetal brain disruption sequence Collapsed skull, overlapping sutures,scalp ruggae asymmetrical ventriculomegaly, fluid filled

23 Zika Virus Syndrome Ventriculomegaly

24 CNS abnormalities associated with Zika Abnormal cortical formation Lissencephaly a smooth outer brain surface characterized by a paucity of gyral and sulcal development. It is the result of incomplete migration of neurons and cannot be reliably suspected before weeks gestation Schizencephaly is characterized by the presence of CSF filled clefts of cerebral hemispheres that extend from the cortical surface to ventricle and are lined by dysplastic gray matter

25 Brain Abnormalities Associated with Zika Cerebellar abnormalities hydranencephaly

26 Birth defects potentially related to Zika virus infection Other major brain abnormalities including intraventricular hemorrhage Neural tube defects including anencephaly, acrania, encephalocele and spina bifida

27 Birth defects potentially related to Zika Virus Infection Eye Abnormalities: Micropthalmia, anopthalmia,coloboma, cataracts, intraocular calcifications, chorioretinal anomalies involving the macula

28 Eye Abnormalities

29 Eye abnormalities

30 Musculoskeletal malformations and Zika The musculoskeletal findings and malformations present in Congenital Zika Syndrome are probably not the result of direct cytopathic effect of the virus on the affected tissues, but are secondary to ZIKV induced brain injury. Reduction of fetal mobility resulting from intrauterine infection occurring in early development is a well known cause of arthrogryposis, fetal akinesia deformation sequence, and related malformations.

31 Birth defects potentially related to Zika Virus infection Congenital contractures (eg, arthrogryposis, clubfoot, congenital hip dysplasia) with associated brain abnormalities

32 Timing of Infection and Zika effects It seems likely that the first trimester is the gestational period when the fetus is most sensitive to ZIKV microcephaly One study found no adverse outcomes among women who were infected with ZIKV during their third trimester Other reports found various adverse outcomes including placental insufficiency, intrauterine growth restriction, cerebral calcifications,as well as microcephaly following ZIKV infection at various stages of gestation even in mothers who were asymptomatic suggesting that the severity of maternal illness may not predict outcomes Fetal demise has been reported in women who were infected as late as weeks gestation

33 Rubella timing of injury

34 Vertical transmission

35 Vertical transmission

36 Vertical Transmission Vertical transmission of pathogens from mother to fetus can occur by several routes: Infection of endothelial cells in the maternal microvasculature and spread to invasive extravillous trophoblasts(evt s) which are the cells that anchor the villous trees to the uterine wall Trafficking of infected maternal immune cells across the placental barrier Paracellular or transcellular transport (for example immunoglobulin mediated transcytosis) from maternal blood across the villous trees and into the fetal capillaries Damage to the villous trees and breaks in the SYN layer

37 Vertical transmission Transvaginal ascending infection

38 How Zika infects the placenta Zika virus can infect and replicate immune cells from the placenta without killing them This finding may explain how the virus can pass through the placenta on its way to infect developing brain cells in the fetus Scientists found that the virus could infect placental macrophages,(called Hofbauer cells) as well as cytotrophoblasts The cells utilized were derived from full term placentas obtained from healthy volunteers. The level of viral replication varied markedly suggesting that host genetics, nutrition and microbiota may be influencing infectivity. Placental macrophages being infected by the Zika virus (zika antigens are red, blue shows the cell nucleus, green the cytoskeletal protein,actin)

39 Hyperplasia of Hofbauer Cells Hyperplasia of Hofbauer cells is abnormal and occurs in ascending infections, villitis of unknown etiology,and maternal blood borne TORCH infections like syphilis, Chagus disease and cytomegalovirus infection. Zika virus can infect and replicate in human Hofbauer cells. These cells may inhibit or facilitate transplacental transmission of infectious agents such as Zika virus.

40 Zika kills stem cells in the brain ZIKV kills stem cells in the brain and disrupts the process of creating brain cells. An analysis shows that the virus diverts form of protein TBK1 from its primary job of organizing cell division. Lacking the protein at the site of cell division, cells die instead of forming new brain cells, resulting in microcephaly

41 Zika infects amniotic epithelial cells Staining of amniotic stem cells indicates that ZIKV replicates in pluripotent cells involved in early stage embryo development. This suggests that Zika may predominantly affect neural precursor cells, and attenuates growth of human neural progenitor cells

42 Zika infects neuroprogenitor cells in culture

43 Brain Development

44 JB1 Congenital disorders induced by TORCH pathogens and ZIKV are remarkable particularly with respect to their neurotropism Similar to ZIKV, fetal infection by T.gondii, rubella virus, CMV, VZV and other pathogens are associated with microcephaly the fetal brain disruption sequence seems to be uniquely characteristic of ZIKV associated microcephaly. ZIKV produces a cytopathic effect and lack of inflammation in brain histopathology that are reminiscent of congenital rubella syndrome. CMV Lesions And hydrops

45 Slide 44 JB1 Jacquelyn Blackstone, 1/15/2017

46 Comparisons between Congenital Malformations from TORCH infections and ZIKA Virus The specific malformations that are induced by TORCH pathogens, ( and probably ZIKA), depend on the gestational age at fetal infection. Rubella virus in the first trimester is associated with high rates of miscarriage and with the most severe congenital malformations. As pregnancy progresses the risk of malformations decreases and becomes very low during and after the second trimester.

47 Ventriculomegaly in Herpes Simplex fetus TORCH and CNS anomalies CMV, HSV (type 1 and 2), varicella zoster and chikungunya virus also cause congenital CNS malformations Fetal brain abnormalities are also caused by syphilis, toxoplasmosis HIV, measles, rubella, and parvovirus B 19 Other causes of microcephaly include drug use, alcohol consumption, smoking, various medications

48 Toxoplasmosis and CNS abnormalities

49 TORCHZ? The similarities between the congenital disorders that are induced by the TORCH pathogens suggest that Zika be considered a new member of the TORCH family of pathogens(microorganisms associated with known congenital disease): Toxoplasmosis gondii Listeria monocytogenes Treponema pallidum Varicella zoster virus (VZV) Human Immunodeficiency Virus (HIV) Parvovirus B 19 Rubella virus Cytomegalovirus(CMV) Herpes Simplex Virus (HSV 1&2)

50 TORCHZ? Microcephaly was the first congenital abnormality that was associated with ZIKV infection, probably owing to its dramatic presentation. Similar to other TORCH pathogens, ZIKV probably causes a range of developmental abnormalities and should probably be characterized as the as the Zika Virus Syndrome as we learn more about its variable manifestations. As with other TORCH infections the long term effects may not be apparent at birth and are often diagnosed as the child develops, especially regarding more subtle effects such as hearing loss, cognitive and behavioral impairments, or other as yet unknown complications.

51 TORCHZ? The available evidence indicates that Zika infection during pregnancy can result in transplacental transmission and fetal damage. Whether there are co factors such as environment, viral strain differences, co infections, natural immune responses or host genetics remains to be seen.

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53 Zika What next? The unprecedented size of the current epidemic is probably a consequence of the emergence of the virus in an immunologically naïve population. The incidence of ZIKV infection is likely to decline in the presence of substantial population immunity There is no evidence that prior ZIKV infection affects future pregnancies exposure to the virus before a girl reaches child bearing age should decrease the future risk of ZIKV related birth defects through immunity

54 Zika what next? Experience in Latin America with DENV and Chickungunya viruses, which are spread by the same mosquito vectors, suggests that continued ZIKV outbreaks and adult infections are likely. This highlights the need for a vaccine to ensure that women of childbearing age are immune to ZIKV, much as routine immunization with the measles mumps rubella vaccine has eliminated congenital rubella syndrome from the Americas.

55 Zika what to do now?

56 Zika What to do Now?

57 Zika what to do now?

58 Zika What to do now?

59 Zika what to do now?

60 Zika what to do now?

61 Management of a Zika Exposed Pregnancy Go to ACOG /CDC websites constantly updated, easy to use To decide if Zika testing is needed Does your pregnant pt live in an area with active Zika virus transmission? yes Has your pregnant pt previously lived in or traveled to an area with active Zika virus transmission during pregnancy or in the periconceptual period? yes Does your pregnant pt have one or more symptoms consistent with Zika virus disease? no Is the pt in her 1 st or 2 nd trimester? yes Order Zika virus IgM antibody test Collect serum and urine specimens (detailed instructions given, send to local or state public health lab as per CDC guidelines)

62 To decide if Zika testing is needed Does pt live in area with active Zika virus transmission? no Has the pt previously lived in or traveled to an area with active Zika virus transmission during pregnancy or the periconceptional period (defined as eight weeks before conception or six weeks before last menstrual period) no Has your pregnant pt had sex ( vaginal, anal, or oral sex) without a condom with a partner(s) who lives in or has traveled to an area with active Zika virus transmission. yes Does your pregnant pt have one or more symptoms consistent with Zika virus disease? yes How long ago did symptoms begin?

63 To Decide if Zika testing is needed (continued) ~ If symptoms began <2 weeks ago 1. order Zika rrt PCR/ nuceic acid test (NAT test) 2. collect serum and urine specimens and/or other specimens deemed appropriate by the public health or commercial lab performing your testing. Collect enough so that reflex testing can occur if needed. 3. consider storing samples for further testing that might be needed. ~If symptoms began 2 12 weeks ago 1.order zika virus IgM and dengue virus IgM tests 2. collect serum and urine samples and /other specimens deemed appropriate. Collect enough specimens so that reflex testing can occur if needed. 3. Consider storing samples for further testing that might be needed.

64 To Decide if Zika testing is needed (continued) ~If symptoms began >12 weeks ago: Clinical Management: for symptomatic and asymptomatic pregnant women with possible Zika virus exposure who seek care >12 weeks after symptom onset or possible exposure, IgM antibody testing might be considered. ~If fetal abnormalities are present, rrt PCR testing should also be performed on maternal serum and urine. However, a negative IgM antibody test or rrt PCR result> 12 weeks after symptom onset or possible exposure does not rule out recent Zika virus infection Because IgM antibody and viral RNA levels decline over time. Given the limitations of testing beyond 12 weeks after symptom onset or possible exposure, serial fetal ultrasounds should be considered.

65 Recommendations for Prenatal Management Consider every serial ultrasounds 3 4 weeks to assess fetal anatomy and growth.(congenital Zika virus syndrome may include microcephaly, intracranial calcifications, ventriculomegaly, arthrogryposis, abnormalities of the corpus callosum, cerebrum, cerebellum, and eyes) Decisions regarding amniocentesis should be individualized for each clinical circumstance Notify state, tribal, local,or territorial health department staff or CDC registry staff of adverse events ( e.g., birth defects, pregnancy losses, abnormal ultrasound findings) Please check current guidance updates

66 How to interpret INITIAL test results Choose test performed: ~Zika virus RRT PCR on serum and urine ~Zika virus IgM on serum yes ~Zika virus IgM and dengue IgM on serum What were the results of the IgM tests? ~Zika IgM negative yes ~Zika IgM positive Interpretation: no evidence of Zika or dengue virus infections. Recommendation: Prenatal ultrasound to evaluate for fetal abnormalities consistent with congenital Zika virus syndrome. If fetal abnormalities are present, repeat Zika virus rrt PCR and IgM test: manage based on lab results

67 Interpreting INITIAL test results (ACOG SITE) Choose initial test performed (Zika virus rrt PCR on serum and urine, Zika virus IgM on serum, Zika virus IgM and dengue IgM on serum) What were the results of the Zika virus rrt PCR on serum or urine?(if answer positive on either serum or urine)then test results suggest recent maternal Zika virus infection Report your pt to US Zika Pregnancy Registry as well as report laboratory evidence to your state, tribal, local, or territorial health department. ( If you have questions you can or call the Zika Pregnancy Hotline at Is the pt still pregnant?

68 How to interpret initial test results If zika IgM positive or equivocal Interpretation: testing results suggest presumptive recent Zika virus or presumptive recent flavivirus infection. Action needed: Reflex rrt PCR testing should be automatically performed on the IgM positive serum sample and a urine sample ( if available) to determine whether Zika virus RNA is present. (If no stored sample is available, pt will need to submit a new sample) Clinical management: test results indicate presumptive recent zika or flavivirus infection, but specific virus cannot be identified. Is pt still pregnant? yes Consider serial ultrasounds every 3 4 weeks to assess fetal anatomy and growth. Consider amniocentesis. Report pt to US Zika Pregnancy Registry

69 Interpreting subsequent test results and management Zika virus IgM or dengue virus IgM (after previous negative rrt PCR result) ~If both Zika IgM and dengue IgM were NEGATIVE Interpretation: no evidence of Zika or dengue virus infection. Recommendation:Prenatal ultrasound to evaluate for fetal abnormalities. if fetal abnormalities are present, repeat Zika virus rrt PCR and IgM test; manage based on lab results if fetal abnormalities are absent, base obstetric care on the ongoing risk of Zika virus exposure in pregnant women.

70 Interpreting Subsequent test results and management Zika virus rrt PCR on serum and urine ( after previous POSITIVE Zika IgM result) ~ if reflex Zika rrt PCR is NEGATIVE Interpretation suggests presumptive recent Zika virus or presumptive recent flavivirus infection Action needed: Plaque reduction neutralization test(prnt) for Zika and dengue viruses ( or other flaviviruses endemic to the region where exposure occurred) should be automatically performed on the same IgM tested sample or a subsequently collected sample. Clinical management:(assuming recent Zika or flavivirus infection based on test results). Consider serial ultrasounds every 3 4 weeks for fetal anatomy and growth. Consider amnio. Report pt to US Zika Pregnancy Registry

71 Interpreting Subsequent test results and management Plaque reduction neutralization test (PRNT)` ~ if Zika virus PRNT>=10 AND dengue virus<10 Interpretation:reults suggest recent Zika infection Recommend: serial ultrasounds every 3 4 weeks for fetal anatomy and growth. Consider amniocentesis. Notify state, tribal, local or territorial health department or CDC of adverse events. ~if Zika virus PRNT>=10 AND dengue virus PRNT>=10 Interpretation:results suggest recent flavivirus infection, but Recommend: serial ultrasounds every 3 4 weeks to assess fetal anatomy and growth. Consider amniocentesis. Notify appropriate agency.

72 Interpreting Subsequent test results and management Plaque Reduction Neutralization test(prnt) ~ if Zika virus PRNT <10 Interpretation: No evidence of Zika virus or dengue infection Recommendation:serial ultrasounds every 3 4 weeks to evaluate for fetal abnormalities and growth. if fetal abnormalities are present, repeat Zika virus rrt PCR and IgM test and base clinical management on lab results if fetal abnormalities are absent, base care on ongoing risk of Zika virus exposure in pregnant women.

73 Next steps for pt who has already received a negative rrt PCR result within 2weeks of possible exposure and returned 2 12 weeks later for a Zika IgM test Action needed: 1.Order Zika virus IgM antibody test. 2. collect serum and urine specimens. Collect enough specimen so that reflex testing can occur if needed. 3. Consider storing additional samples for further testing that might be needed. To Order test: Visit CDC S collecting and submitting bodily fluid.